RESUMEN
A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Pirazoles/química , Sirtuina 1/antagonistas & inhibidores , Sirtuina 2/antagonistas & inhibidores , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Simulación de Dinámica Molecular , Unión Proteica , Pirazoles/síntesis química , Pirazoles/metabolismo , Sirtuina 1/metabolismo , Sirtuina 2/metabolismo , Relación Estructura-ActividadRESUMEN
A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. The original hit, N-hydroxy-2,2-diphenylacetamide (6), has sub-micromolar class IIa HDAC inhibitory activity, while the rigidified oxygen analogue, N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7 with an IC(50) of 0.05muM. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.
Asunto(s)
Ácidos Difenilacéticos/química , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/química , Xantenos/química , Línea Celular , Ácidos Difenilacéticos/síntesis química , Ácidos Difenilacéticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Relación Estructura-Actividad , Xantenos/síntesis química , Xantenos/farmacologíaRESUMEN
Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Homocisteína/análogos & derivados , Pirrolidinas/síntesis química , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Homocisteína/síntesis química , Homocisteína/farmacología , Humanos , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-ActividadRESUMEN
The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , S-Adenosilhomocisteína/síntesis química , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , S-Adenosilhomocisteína/química , S-Adenosilhomocisteína/farmacología , Relación Estructura-ActividadRESUMEN
We have recently reported on a novel class of histone deacetylase (HDAC) inhibitors bearing a sulfamide group as the zinc-binding unit. Herein, we report on the synthesis of sulfamide based inhibitors designed around a lysine scaffold and their structure-activity relationships against HDAC1 and HDAC6 isotypes as well as 293T cells. Our efforts led us to an improvement of the originally disclosed lysine-based sulfamide, 2a to compound 12h which has equal potency in enzyme and cell-based assays as well as enhanced metabolic stability and PK profile.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Bencimidazoles/farmacocinética , Proteínas Portadoras/química , Línea Celular , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Histona Desacetilasas/metabolismo , Humanos , Lisina/química , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Asunto(s)
Amidas/química , Imidazolidinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Amidas/farmacología , Animales , Línea Celular Tumoral , Células HCT116 , Humanos , Imidazolidinas/farmacología , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/química , Acetilación , Dominio Catalítico , Química Farmacéutica/métodos , Diseño de Fármacos , Histona Desacetilasa 6 , Histona Desacetilasas/metabolismo , Histonas/química , Humanos , Ácidos Hidroxámicos/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Piperazina , Piperazinas/química , Isoformas de Proteínas , Tubulina (Proteína)/químicaRESUMEN
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/farmacología , Benzamidas/síntesis química , Línea Celular Tumoral , Proliferación Celular , Química Farmacéutica/métodos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores de Histona Desacetilasas , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.
Asunto(s)
Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona DesacetilasasRESUMEN
The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Perros , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.
Asunto(s)
Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/farmacología , Acetilación , Animales , Benzamidas/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Femenino , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Isoenzimas , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Pirimidinas/farmacocinética , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Células Tumorales Cultivadas , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.
Asunto(s)
Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Humanos , Ratones , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Piridinas/síntesis química , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
Asunto(s)
Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Compuestos de Anilina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Mama/citología , Mama/efectos de los fármacos , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidores Enzimáticos/química , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células HCT116 , Histona Desacetilasa 1 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Relación Estructura-ActividadRESUMEN
Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Triazinas/síntesis química , Triazinas/farmacología , Animales , Antineoplásicos/química , Benzamidas/química , Modelos Animales de Enfermedad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Aminación , Animales , Sitios de Unión , Línea Celular , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Metilación , Ratones , Modelos Moleculares , Estructura Molecular , Niacina/farmacología , Relación Estructura-Actividad , Urea/química , Vasodilatación/efectos de los fármacos , ortoaminobenzoatos/químicaRESUMEN
Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Inhibidores de Histona Desacetilasas , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Antineoplásicos/química , Benzamidas/química , Benzamidas/farmacología , Dominio Catalítico , Línea Celular , Histona Desacetilasa 1 , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Modelos Moleculares , NADH NADPH Oxidorreductasas/química , NADH NADPH Oxidorreductasas/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.