RESUMO
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.
Assuntos
Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/química , Mama/citologia , Mama/efeitos dos fármacos , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidores Enzimáticos/química , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células HCT116 , Histona Desacetilase 1 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Pirimidinas/farmacologia , Triazinas/síntese química , Triazinas/farmacologia , Animais , Antineoplásicos/química , Benzamidas/química , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Camundongos , Relação Estrutura-Atividade , Triazinas/químicaRESUMO
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.
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Aminação , Animais , Sítios de Ligação , Linhagem Celular , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Metilação , Camundongos , Modelos Moleculares , Estrutura Molecular , Niacina/farmacologia , Relação Estrutura-Atividade , Ureia/química , Vasodilatação/efeitos dos fármacos , ortoaminobenzoatos/químicaRESUMO
There is a currently growing interest in the development of histone deacetylase inhibitors (HDACs) as anticancer agents. Histone deacetylases are critically important in the functional regulation of gene transcription as well as in chromatin structure remodeling. A number of small molecule inhibitors of HDAC, such as the naturally occurring trichostatin A (TSA), as well as synthetic compounds, such as suberoylanilide hydroxamic acid (SAHA), scriptaid, oxamflatin or MS-275, have been reported to induce differentiation of several cancer cell lines and suppress cell proliferation. This article will review the recent progress being made in our laboratories in the development of two new families of potent HDAC inhibitors: sulfonamide hydroxamic acids and anilides, as well as TSA-like straight chain derivatives. Some of these compounds inhibit partially purified recombinant human HDAC enzymes with IC(50)'s in the micromolar to low nanomolar range and can induce hyperacetylation of histones in human cancer cells. These compounds significantly inhibit proliferation, induce expression of p21(WAF1/Cip1), and cause cell cycle arrest in various human cancer cells. The lead candidates were screened in a panel of human tumor and normal cell lines. The inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and may be used in future cancer therapies. The structure-activity relationships, the antiproliferative activity and the in vivo efficacy are discussed.
Assuntos
Anilidas/síntese química , Antineoplásicos/síntese química , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/síntese química , Acetilação , Anilidas/química , Anilidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/química , Acetilação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Western Blotting , Divisão Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histonas/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of sulfonamide hydroxamic acids and anilides have been synthesized and studied as histone deacetylase (HDAC) inhibitors that can induce hyperacetylation of histones in human cancer cells. The inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation. The lead candidates were screened in a panel of human tumor and normal cell lines. They selectively inhibit proliferation, cause cell cycle blocks, and induce apoptosis in human cancer cells but not in normal cells. The structure-activity relationships, the antiproliferative activity, and the in vivo efficacy are described.
Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/síntese química , Sulfonamidas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Transplante HeterólogoRESUMO
[structure: see text] The total synthesis of the polyether antibiotic ionomycin, a calcium ionophore, is described. The synthesis demonstrates the utility of ring-opening methodologies as applied to the synthesis of polypropionate and deoxypolypropionate subunits, which are found in two of the four fragments in the synthesis.
Assuntos
Antibacterianos/síntese química , Ionomicina/síntese química , Aldeídos/química , Cálcio/química , Hidroxilação , Indicadores e Reagentes , Ozônio/química , EstereoisomerismoRESUMO
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.
Assuntos
Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Pirimidinas/farmacologia , Administração Oral , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acrilamidas/farmacologia , Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Acrilamidas/química , Benzamidas/química , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Humanos , Relação Estrutura-AtividadeRESUMO
A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.