RESUMO
OBJECTIVE: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. METHODS: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. RESULTS: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. CONCLUSION: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.
Assuntos
Mieloma Múltiplo , Humanos , Camundongos , Animais , Mieloma Múltiplo/patologia , Espécies Reativas de Oxigênio , Cromatografia Líquida , Camundongos Endogâmicos ICR , Linhagem Celular Tumoral , Camundongos SCID , Espectrometria de Massas em Tandem , Recidiva Local de Neoplasia , ApoptoseRESUMO
New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas' disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20â¯mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.
Assuntos
Apoptose/efeitos dos fármacos , Diterpenos/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mieloma Múltiplo/patologia , Oxigênio/metabolismo , Quinonas/química , Animais , Linhagem Celular Tumoral , Diterpenos/farmacologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Xenoenxertos , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Quinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Lamiaceae/química , Mieloma Múltiplo/tratamento farmacológico , Quinonas/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Mieloma Múltiplo/patologia , Quinonas/síntese química , Quinonas/química , Relação Estrutura-AtividadeRESUMO
Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid ß-protein (Aß) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aß oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aß-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , ATPase Trocadora de Sódio-Potássio/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Células HEK293 , Homeostase/efeitos dos fármacos , Humanos , Espectrometria de Massas , Modelos Biológicos , Modelos Moleculares , Imagem Molecular , Dados de Sequência Molecular , Peso Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Peptídeos/metabolismo , Agregados Proteicos , Ligação Proteica/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/químicaRESUMO
Current chemotherapy drugs for Chagas' disease are insufficient due to their limited efficacy; however, anti-trypanosomal agents have recently shown promise. As such, synthetic intermediates of komaroviquinone were evaluated for anti-trypanosomal activity. Based on the results, a series of novel quinone derivatives were screened for anti-trypanosomal activity and mammalian cytotoxicity. Several quinone derivatives displayed higher antiprotozoal activity against Trypanosoma cruzi trypomastigotes than the reference drug benznidazole, without concomitant toxicity toward the host cell.
Assuntos
Doença de Chagas/tratamento farmacológico , Diterpenos/química , Diterpenos/farmacologia , Quinonas/química , Quinonas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Células 3T3 , Animais , Doença de Chagas/parasitologia , Diterpenos/síntese química , Humanos , Camundongos , Quinonas/síntese química , Tripanossomicidas/síntese químicaRESUMO
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Assuntos
Catepsinas/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Catepsina L , Técnicas de Química Combinatória , Cisteína Endopeptidases , Humanos , Masculino , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Dor/tratamento farmacológico , Pirimidinas/sangue , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Animais , Medula Óssea/metabolismo , Catepsina K , Colágeno Tipo I/metabolismo , Haplorrinos , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Compostos de Espiro , Distribuição TecidualRESUMO
Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.
Assuntos
Analgésicos/uso terapêutico , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Inibidores de Cisteína Proteinase/administração & dosagem , Inibidores de Cisteína Proteinase/farmacocinética , Doenças do Sistema Nervoso Periférico/enzimologia , RatosRESUMO
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Assuntos
Catepsinas/antagonistas & inibidores , Química Farmacêutica/métodos , Inibidores de Cisteína Proteinase/síntese química , Nitrilas/síntese química , Peptídeos/química , Pirimidinas/química , Pirimidinas/síntese química , Animais , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Conformação Molecular , Nitrilas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.
Assuntos
Catepsinas/antagonistas & inibidores , Cisteína Endopeptidases/síntese química , Inibidores de Cisteína Proteinase/síntese química , Disponibilidade Biológica , Catepsina K , Catepsina L , Catepsinas/química , Química Farmacêutica , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Cyano pyrimidine acetylene and cyano pyrimidine t-amine, which belong to a new chemical class, were prepared and tested for inhibitory activities against cathepsin K and the highly homologous cathepsins L and S. The use of novel chemotypes in the development of cathepsin K inhibitors has been demonstrated by derivatives of compounds 1 and 8.
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Sítios de Ligação , Catepsina K , Catepsina L , Catepsinas/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.