RESUMEN
Aldehyde dehydrogenase 2 (ALDH2) plays important role in ethanol metabolism, and also serves as an important shield from the damage occurring under oxidative stress. A special inactive variant was found carried by 35-45% of East Asians. The variant carriers have recently been found at the higher risk for the diseases related to the damage occurring under oxidative stress, such as cardiovascular and cerebrovascular diseases. As a result, ALDH2 activators may potentially serve as a new class of therapeutics. Herein, N-benzylanilines were found as novel allosteric activators of ALDH2 by computational virtual screening using ligand-based and structure-based screening parallel screening strategy. Then a structural optimization was performed and has led to the discovery of the compound C6. It has good activity in vitro and in vivo, which could reduce infarct size by â¼70% in ischemic stroke rat models. This study provided good lead compounds for the further development of ALDH2 activators.
Asunto(s)
Aldehído Deshidrogenasa Mitocondrial/metabolismo , Descubrimiento de Drogas , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Infarto de la Arteria Cerebral Media/patología , Accidente Cerebrovascular Isquémico/patología , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Modelos Moleculares , Estructura Molecular , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Relación Estructura-ActividadRESUMEN
The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL (E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Dominio Catalítico , Línea Celular Tumoral , Diseño de Fármacos , HumanosRESUMEN
The phosphoinositide 3-kinase (PI3K) family is one of the most frequently activated enzymes in a wide range of human cancers; thus, inhibition of PI3K represents a promising strategy for cancer therapy. Herein, a series of benzylamine substituted arylsulfonamides were designed and synthesized as dual PI3K/mTOR inhibitors using a strategy integrating focused library design and virtual screening, resulting in the discovery of 13b (NSC765844). The compound 13b exhibits highly potent enzyme inhibition with IC50s of 1.3, 1.8, 1.5, 3.8 and 3.8 nM for PI3Kα, ß, γ, δ, and mTOR, respectively. 13b was further evaluated in NCI by an in vitro cytotoxic screening program. Broad-spectrum antitumor activities with mean GI50 value of 18.6 nM against approximately 60 human tumor cell lines were found. 13b displayed favorable physicochemical properties and superior pharmacokinetic profiles for animal studies. It significantly inhibited tumor growth when administered orally in an A549 non-small-cell lung carcinoma xenograft and BEL7404 human hepatocellular carcinoma xenograft models. On the basis of its excellent in vivo efficacy and superior pharmacokinetic profiles, 13b has been selected for further preclinical investigation as a promising anticancer drug candidate.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Secuencia de Aminoácidos , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Masculino , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Conformación Proteica , Ratas , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Sulfonamidas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The luteolin from Flos Chrysanthemi was found to directly bind to the Bcl-2 protein and inhibit the tumor cell growth in our previous study. However, it has been shown to possess wide and week biological activities. In this study, a series of derivatives of luteolin were designed and synthesized, and their tumor cell growth inhibitory activities were evaluated against human leukemia cell line HL-60. The results showed that compounds 1B-2, 2A-3, and 2B-5, with hydrophobic substituted benzyl groups introduced to B ring and hydrogen or methyl introduced to 7-OH group of luteolin, exhibited the strongest inhibitory activity with the IC50 lower than 10µM, which were significantly more potent than luteolin. The studies presented here offer a good example for modifications of flavones to improve their tumor cell growth inhibitory activities.