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1.
Eur J Med Chem ; 176: 195-207, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103900

RESUMO

Previously, we focused on a series of 2-aminobenzamide-based histone deacetylase (HDAC) inhibitors, compound 9 of which displayed potent HDAC inhibitory activity against HDAC1 and HDAC2, and moderate anti-proliferative activity against several cancer cell lines. In the current study, we have designed and synthesized a series of novel HDAC inhibitors based on thioether moiety with 9 as a lead compound. Representative compounds12 g and 12 h showed apparently potent anti-proliferative activities against five solid cancer cell lines: A549, HCT116, Hela, A375 and SMMC7721, and low cytotoxicity against NIH 3T3 normal cells. Especially, 12 g and 12 h also revealed potent HDAC inhibitory activity against HDAC1, 2 and 3. In addition, the two compounds could arrest cell cycle in G2/M phase and promote cell apoptosis. Moreover, they showed extended inhibition of colony formation and effectively blocked cell migration towards A549 cancer cells. Furthermore, 12 g and 12 h possessed better pharmacokinetic properties than the lead compound 9. Benefiting from these results, we also explored 12 g and 12 h in the A549 xenografts model for in vivo antitumor activity. The in vivo experiment indicated that 12 g and 12 h could evidently augment antitumor activity (TGI = 56.9% and 62.7% respectively).


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Sulfetos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Humanos , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Sulfetos/síntese química , Sulfetos/farmacocinética , Sulfetos/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
ChemMedChem ; 14(9): 912-926, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30664827

RESUMO

Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure-activity and structure-toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, with IC50 values in the range of 0.0052-0.25 µm and promising selectivity over mammalian cells (SIPf3D7/HepG2 : 170-1483). In addition, several compounds showed encouraging sub-micromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide (2 h) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC50 Pf3D7=0.0052 µm, IC50 PbEEF=0.016 µm).


Assuntos
Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Peptoides/química , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Acetilação , Animais , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/toxicidade , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade
3.
Drug Chem Toxicol ; 42(5): 526-535, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29681204

RESUMO

The aims of the present research are to further validate the application of the improved three-dimensional (3 D) rat testicular cell co-culture model to evaluate the effects of various reprotoxic chemicals on the function of the main somatic cells, as well as on spermatogonial cell differentiation and even spermatogenesis, and to investigate the specific toxicant mechanisms in testes treated with HZ1006, a hydroxamate-based a hydroxamate-based histone deacetylase inhibitor (HDACI). Based on the characteristics of HZ1006, the appropriate exposure duration (8, 16, or 24 days), dosage (0, 3.125, 6.25, 12.5, or 25 µM) and toxic endpoints suitable for detection were selected in the experiments. The results showed inhibition of cell proliferation, reduced testosterone levels, and decreased spermatogonial cell meiosis-specific gene expression, as well as decreased protein levels of androgen receptor (AR) and decreased expression of the AR target gene PSA, accompanied by inhibition of Hdac6 expression after HZ1006 exposure in the 3 D rat testicular cell co-culture model. These findings indicate that the improved 3 D rat testicular cell co-culture model we have established has the potential to become a new testicular toxicity test system that can be used to test toxic characteristics and mechanisms of new compounds and has good application prospects, although more research on the model is required.


Assuntos
Cinamatos/toxicidade , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Espermatogônias/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/química , Técnicas de Cocultura , Feminino , Inibidores de Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Masculino , Estrutura Molecular , Ratos Sprague-Dawley , Espermatogônias/metabolismo , Espermatogônias/patologia , Testículo/metabolismo , Testículo/patologia , Testosterona/metabolismo
4.
Toxicol Appl Pharmacol ; 350: 43-51, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29733868

RESUMO

Histone deacetylases (HDACs), which regulate transcription and specific functions such as tumor suppression by p53, are frequently altered in tumors and have a contentious role in carcinogenesis. HDAC inhibitors, which have a long history of use in psychiatry and neurology, have recently been tested as possible treatments for tumors. Belinostat received regulatory approval in the USA on July 3, 2014, for use against peripheral T-cell lymphoma. However, the unavailability of information on belinostat genotoxicity in normal cells and the molecular mechanisms involved in the genetic instability after exposure to belinostat encouraged us to conduct this study. Our data showed that the exposure of mice to belinostat at the recommended human doses induced chromosome breakage, whole-chromosome lagging, and oxidative DNA damage in bone marrow cells in a dose-dependent manner. The expression levels of 84 genes involved in the DNA damage signaling pathway were evaluated by using an RT2 Profiler PCR array. Belinostat exposure altered the expression of 25 genes, with statistically significant changes observed in 17 genes. The array results were supported by RT-PCR and western blotting experiments. Collectively, our results showed that belinostat exposure caused oxidative DNA damage and downregulated the expression of genes involved in DNA damage repair, which may be responsible for belinostat-induced genomic instability. Thus, the clinical usage of this drug should be weighed against the hazards of carcinogenesis, and the observed genotoxicity profile of belinostat may support further development of efficient HDAC inhibitors with weaker genotoxicity.


Assuntos
Análise Citogenética/métodos , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica/efeitos dos fármacos , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/toxicidade , Animais , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Relação Dose-Resposta a Droga , Instabilidade Genômica/fisiologia , Masculino , Camundongos , Transdução de Sinais/fisiologia
5.
J Med Chem ; 61(8): 3454-3477, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29589441

RESUMO

Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-ß-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Benzamidas/uso terapêutico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Antirreumáticos/síntese química , Antirreumáticos/farmacologia , Antirreumáticos/toxicidade , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Benzamidas/líquido cefalorraquidiano , Benzamidas/farmacologia , Benzamidas/toxicidade , Sítios de Ligação , Carbolinas/síntese química , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Carbolinas/toxicidade , Linhagem Celular Tumoral , Colágeno Tipo II , Células HEK293 , Desacetilase 6 de Histona/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/toxicidade , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Ácidos Hidroxâmicos/toxicidade , Masculino , Camundongos Endogâmicos DBA , Simulação de Acoplamento Molecular , Peixe-Zebra
6.
Int J Mol Sci ; 19(1)2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29304031

RESUMO

Neuroblastoma (NBL) originates from undifferentiated cells of the sympathetic nervous system. Chemotherapy is judged to be suitable for successful treatment of this disease. Here, the influence of histone deacetylase (HDAC) inhibitor valproate (VPA) combined with DNA-damaging chemotherapeutic, ellipticine, on UKF-NB-4 and SH-SY5Y neuroblastoma cells was investigated. Treatment of these cells with ellipticine in combination with VPA led to the synergism of their anticancer efficacy. The effect is more pronounced in the UKF-NB-4 cell line, the line with N-myc amplification, than in SH-SY5Y cells. This was associated with caspase-3-dependent induction of apoptosis in UKF-NB-4 cells. The increase in cytotoxicity of ellipticine in UKF-NB-4 by VPA is dictated by the sequence of drug administration; the increased cytotoxicity was seen only after either simultaneous exposure to these drugs or after pretreatment of cells with ellipticine before their treatment with VPA. The synergism of treatment of cells with VPA and ellipticine seems to be connected with increased acetylation of histones H3 and H4. Further, co-treatment of cells with ellipticine and VPA increased the formation of ellipticine-derived DNA adducts, which indicates an easier accessibility of ellipticine to DNA in cells by its co-treatment with VPA and also resulted in higher ellipticine cytotoxicity. The results are promising for in vivo studies and perhaps later for clinical studies of combined treatment of children suffering from high-risk NBL.


Assuntos
Elipticinas/toxicidade , Inibidores de Histona Desacetilases/toxicidade , Mutagênicos/toxicidade , Neurônios/efeitos dos fármacos , Ácido Valproico/toxicidade , Apoptose , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Neuroblastoma/metabolismo , Neurônios/metabolismo
7.
Bioorg Med Chem ; 26(3): 747-757, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29317150

RESUMO

Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven't been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 µM in vitro. Meanwhile, the compound also exhibited moderate FGFR1 inhibitory activities. This study provides new tool compounds for further exploration of dual HDAC/FGFR1 inhibition.


Assuntos
Desenho de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Indazóis/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/toxicidade , Humanos , Indazóis/toxicidade , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Relação Estrutura-Atividade
8.
Int J Mol Sci ; 18(12)2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215575

RESUMO

Effective DNA repair enables cancer cells to survive DNA damage induced by chemotherapeutic or radiotherapeutic treatments. Therefore, inhibiting DNA repair pathways is a promising therapeutic strategy for increasing the efficacy of such treatments. In this study, we found that dihydrocoumarin (DHC), a flavoring agent, causes deficiencies in double-stand break (DSB) repair and prolonged DNA damage checkpoint recovery in yeast. Following DNA damage, Rad52 recombinase was revealed to be inhibited by DHC, which results in deficiencies in DSB repair and prolonged DNA damage checkpoint recovery. The deletion of RPD3, a class I histone deacetylase (HDAC), was found to mimic DHC-induced suppression of Rad52 expression, suggesting that the HDAC inhibitor activity of DHC is critical to DSB repair and DNA damage sensitivity. Overall, our findings delineate the regulatory mechanisms of DHC in DSB repair and suggest that it might potentially be used as an inhibitor of the DNA repair pathway in human cells.


Assuntos
Cumarínicos/toxicidade , Dano ao DNA , Aromatizantes/toxicidade , Inibidores de Histona Desacetilases/toxicidade , Proteína Rad52 de Recombinação e Reparo de DNA/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Cumarínicos/farmacologia , Aromatizantes/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Reparo de DNA por Recombinação , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
9.
Bioorg Med Chem Lett ; 27(21): 4885-4888, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947154

RESUMO

A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.


Assuntos
Desenho de Drogas , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Quinazolinas/química , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Meia-Vida , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/química , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo
10.
Chemistry ; 23(60): 15166-15176, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28833658

RESUMO

Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated IrIII complexes have emerged as potential anticancer agents. By conjugation of VPA to IrIII complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1 a-3 a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1 a-3 a can overcome cisplatin resistance effectively and are about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin-resistant human lung carcinoma (A549R) cells. Mechanistic studies indicate that 1 a-3 a can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, accumulate in mitochondria, and induce a series of cell-death-related events mediated by mitochondria. This study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents.


Assuntos
Antineoplásicos/toxicidade , Complexos de Coordenação/química , Irídio/química , Mitocôndrias/efeitos dos fármacos , Ácido Valproico/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cisplatino/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Humanos , Microscopia de Fluorescência por Excitação Multifotônica , Conformação Molecular , Espécies Reativas de Oxigênio/metabolismo
11.
Thromb Haemost ; 117(9): 1722-1729, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28837204

RESUMO

Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. The heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. By using murine models, we aimed to test the hypothesis that overexpressing Hsp70 with CM-695, a first in class dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. Intraperitoneal (i. p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [p=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs 39.0 minutes (min) in the control group (CG), p=0.008, n≥10] and ferric chloride (OT: 14.7 vs 9.2 min in the CG, p=0.032, n≥10) models. I.p. 80 mg/kg CM-695 (n≥9) and intravenous 3 mg/kg rivaroxaban (n≥8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs 7.5 min in the CG, n≥10]. However, BT was dramatically increased by rivaroxaban (30.0 vs 13.7 min in the CG, p=0.001, n=10). In conclusion, CM-695 is a new antithrombotic small molecule devoid of bleeding risk that may be envisioned as a useful clinical tool.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/farmacologia , Proteínas de Choque Térmico HSP70/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Rivaroxabana/farmacologia , Tromboembolia/prevenção & controle , Trombose/prevenção & controle , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Tempo de Sangramento , Feminino , Fibrinolíticos/toxicidade , Proteínas de Choque Térmico HSP70/deficiência , Proteínas de Choque Térmico HSP70/genética , Hemorragia/induzido quimicamente , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/toxicidade , Camundongos , Camundongos Knockout , Doença Autoimune do Sistema Nervoso Experimental , Inibidores de Fosfodiesterase/toxicidade , Medição de Risco , Rivaroxabana/toxicidade , Tromboembolia/sangue , Tromboembolia/genética , Trombose/sangue , Trombose/genética , Fatores de Tempo , Regulação para Cima
12.
Apoptosis ; 22(9): 1169-1188, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28685254

RESUMO

Treatment of leishmaniasis involves the use of antimonials, miltefosine, amphotericin B or pentamidine. However, the side effects of these drugs and the reports of drug-resistant parasites demonstrate the need for new treatments that are safer and more efficacious. Histone deacetylase inhibitors are a new class of compounds with potential to treat leishmaniasis. Herein, we evaluated the effects of KH-TFMDI, a novel histone deacetylase inhibitor, on Leishmania amazonensis promastigotes and intracellular amastigotes. The IC50 values of this compound for promastigotes and intracellular amastigotes were 1.976 and 1.148 µM, respectively, after 72 h of treatment. Microscopic analyses revealed that promastigotes became elongated and thinner in response to KH-TFMDI, indicating changes in cytoskeleton organization. Immunofluorescence microscopy, western blotting and flow cytometry using an anti-acetylated tubulin antibody revealed an increase in the expression of acetylated tubulin. Furthermore, transmission electron microscopy revealed several ultrastructural changes, such as (a) mitochondrial swelling, followed by the formation of many vesicles inside the matrix; (b) presence of lipid bodies randomly distributed through the cytoplasm; (c) abnormal chromatin condensation; and (d) formation of blebs on the plasma membrane. Physiological studies for mitochondrial function, flow cytometry with propidium iodide and TUNEL assay confirmed the alterations in the mitochondrial metabolism, cell cycle, and DNA fragmentation, respectively, which could result to cell death by mechanisms related to apoptosis-like. All these together indicate that histone deacetylases are promising targets for the development of new drugs to treat Leishmania, and KH-TFMDI is a promising drug candidate that should be tested in vivo.


Assuntos
Compostos de Benzilideno/farmacologia , Morte Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Indóis/farmacologia , Leishmania/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sirtuínas/antagonistas & inibidores , Animais , Antiparasitários/farmacologia , Antiparasitários/toxicidade , Apoptose/efeitos dos fármacos , Compostos de Benzilideno/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Inibidores de Histona Desacetilases/toxicidade , Indóis/toxicidade , Concentração Inibidora 50 , Leishmania/citologia , Leishmania/crescimento & desenvolvimento , Leishmania/ultraestrutura , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos
13.
Cell Mol Life Sci ; 74(22): 4171-4187, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28643165

RESUMO

The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.


Assuntos
Neoplasias/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/toxicidade , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/química , Pirimidinas/uso terapêutico , Pirimidinas/toxicidade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores
14.
Bioorg Med Chem ; 25(14): 3677-3684, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28549889

RESUMO

Epigenetic regulation of gene expression via histone acetylation modulates many cellular processes, including apoptosis, the cell cycle, cell growth and differentiation, and inhibitors are promising drug candidates. We have previously developed inhibitors of BRD4, which recognizes acetylated lysine residue on histones and recruits transcription elongation factor to the transcription start site, while inhibitors of histone deacetylase (HDAC), which catalyzes the removal of acetyl groups on histones, are already in clinical use for cancer treatment. Based on the idea that polypharmacological agents with multiple targets would have a more robust action, we set out to develop dual BRD4/HDAC inhibitors. Here, we describe the design and synthesis of N6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d) as a BRD4/HDAC dual inhibitor. This compound showed HL-60 cell growth-inhibitory and apoptosis-inducing activity, as well as all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation-enhancing activity, and c-MYC production-inhibitory activity. Interestingly, it also showed growth-inhibitory activity towards BRD4 inhibitor-resistant cells.


Assuntos
Inibidores de Histona Desacetilases/síntese química , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Acetilação , Adenina/síntese química , Adenina/química , Adenina/toxicidade , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia
15.
Bioorg Med Chem Lett ; 27(4): 744-749, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28131715

RESUMO

The clinical validation of histone deacetylase inhibition as a cancer therapeutic modality has stimulated interest in the development of new generation of potent and tumor selective histone deacetylase inhibitors (HDACi). With the goal of selective delivery of the HDACi to melanoma cells, we incorporated the benzamide, a high affinity melanin-binding template, into the design of HDACi to generate a new series of compounds 10a-b and 11a-b which display high potency towards HDAC1 and HDAC6. However, these compounds have attenuated antiproliferative activities relative to the untargeted HDACi. An alternative strategy furnished compound 14, a prodrug bearing the benzamide template linked via a labile bond to a hydroxamate-based HDACi. This pro-drug compound showed promising antiproliferative activity and warrant further study.


Assuntos
Desenho de Drogas , Inibidores de Histona Desacetilases/síntese química , Acetilação/efeitos dos fármacos , Animais , Benzamidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/toxicidade , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/toxicidade , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Tubulina (Proteína)/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-27916918

RESUMO

Histone deacetylase inhibitors (HDACIs), such as vorinostat and panobinostat, have been shown to have active effects on many hematologic malignancies, including multiple myeloma and cutaneous T-cell lymphoma. Hydroxamate-based (Hb) HDACIs have very good toxicity profiles and are currently being tested in phases I and II clinical trials with promising results in selected neoplasms, such as bladder carcinoma. One of the Hb-HDACIs, HZ1006, has been demonstrated to be a promising drug for clinical use. The aim of our study was to determine the possible target of toxicity and to identify a non-toxic dose of HZ1006 for clinical use. In our studies, the repeated dosage toxicity of HZ1006 in Beagle dogs and Sprague Dawley (SD) rats was identified. Dogs and rats received HZ1006 orally (0-80 and 0-120 mg/kg/day, respectively) on a continuous daily dosing agenda for 28 days following a 14-day dosage-free period. HZ1006's NOAEL (No Observed Adverse Effect Level) by daily oral administration for dogs and rats was 5 mg/kg and 60 mg/kg, respectively, and the minimum toxic dose was 20 and 120 mg/kg, respectively. All the side effects indicated that the digestive tract, the male reproductive tract, the respiratory tract and the hematological systems might be HZ1006 toxic targets in humans. HZ1006 could be a good candidate or a safe succedaneum to other existing HDACIs for the treatment of some solid tumor and hematologic malignancies.


Assuntos
Cinamatos/toxicidade , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Administração Oral , Animais , Análise Química do Sangue , Medula Óssea/efeitos dos fármacos , Cinamatos/farmacocinética , Cães , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Genitália Masculina/efeitos dos fármacos , Hematócrito , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Ácidos Hidroxâmicos/farmacocinética , Pulmão/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Subcrônica
17.
Chem Biol Interact ; 253: 112-24, 2016 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-27163855

RESUMO

Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer. The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 µM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21(Waf1/Cip1) expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1α expression, where the compounds reduced the expression of induced HIF-1α. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13-acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin zymography. Inhibition of malignant cell migration was assessed by scratch wound assay. The compounds showed a decrease in cell migration and inhibition of induced MMP-2 and MMP-9 expression. NMJ-2 exhibited comparable activity to that of standard SAHA. Our findings indicate that NMJ series of compound have potent in vitro anti-cancer, anti-angiogenic and anti-metastatic activity through HDAC enzyme inhibition.


Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Células A549 , Acetilação/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cobalto/toxicidade , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células MCF-7 , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ésteres de Forbol/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Sulfonamidas/química , Tubulina (Proteína)/metabolismo , Proteína Supressora de Tumor p53/metabolismo
18.
Stem Cells Transl Med ; 5(5): 602-12, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27034410

RESUMO

UNLABELLED: Histone deacetylase (HDAC) inhibitors possess therapeutic potential to reverse aberrant epigenetic changes associated with cancers, neurological diseases, and immune disorders. Unfortunately, clinical studies with some HDAC inhibitors displayed delayed cardiac adverse effects, such as atrial fibrillation and ventricular tachycardia. However, the underlying molecular mechanism(s) of HDAC inhibitor-mediated cardiotoxicity remains poorly understood and is difficult to detect in the early stages of preclinical drug development because of a delayed onset of effects. In the present study, we show for the first time in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) that HDAC inhibitors (dacinostat, panobinostat, vorinostat, entinostat, and tubastatin-a) induce delayed dose-related cardiac dysfunction at therapeutic concentrations associated with cardiac adverse effects in humans. HDAC inhibitor-mediated delayed effects on the beating properties of hiPS-CMs developed after 12 hours by decreasing the beat rate, shortening the field potential duration, and inducing arrhythmic behavior under form of sustained contractions and fibrillation-like patterns. Transcriptional changes that are common between the cardiotoxic HDAC inhibitors but different from noncardiotoxic treatments identified cardiac-specific genes and pathways related to structural and functional changes in cardiomyocytes. Combining the functional data with epigenetic changes in hiPS-CMs allowed us to identify molecular targets that might explain HDAC inhibitor-mediated cardiac adverse effects in humans. Therefore, hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and support identification of better HDAC inhibitors with an improved benefit-risk profile. SIGNIFICANCE: Histone deacetylase (HDAC) inhibitors are a promising class of drugs to treat certain cancers, autoimmune, and neurodegenerative diseases. However, treated patients can experience various cardiac adverse events such as hearth rhythm disorders. This study found that human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) can predict cardiac adverse events in patients caused by HDAC inhibitors. Furthermore, transcriptional changes at the level of gene expression supported the effects on the beating properties of hiPS-CMs and highlight targets that might cause these cardiac adverse effects. hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and to support development of safer HDAC inhibitors.


Assuntos
Cardiopatias/induzido quimicamente , Inibidores de Histona Desacetilases/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Potenciais de Ação , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/enzimologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Células Cultivadas , Relação Dose-Resposta a Droga , Epigênese Genética/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Genótipo , Cardiopatias/enzimologia , Cardiopatias/genética , Cardiopatias/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/enzimologia , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Medição de Risco , Fatores de Tempo
19.
Artigo em Inglês | MEDLINE | ID: mdl-26972758

RESUMO

Pharmaceuticals are not currently tested for transgenerational and epigenetic side effects. The use of vertebrates as preclinical research models is limited by their long generation times, low numbers of progeny and ethical concerns. In contrast, invertebrates such as insects breed rapidly, produce many offspring and are more ethically acceptable, allowing them to be used for high-throughput screening. Here, we established Tribolium castaneum as a model to screen for the effect of drugs on complex fitness parameters and the expression of epigenetic regulatory genes. We tested diets supplemented with the psychoactive drug valproic acid (VPA), which is a histone deacetylase inhibitor, or the antioxidant curcumin, which is a histone acetyltransferase inhibitor. We found that VPA delayed development, reduced longevity, and increased female body weight compared to a control diet. Fertility and fecundity declined and the expression of epigenetic regulatory genes was induced in the untreated F1 generation. In contrast, curcumin did not affect development or body weight, but it increased longevity, caused a significant reduction in fertility, and induced the expression of epigenetic regulatory genes mostly in the treated F0 generation. VPA and curcumin administered to vertebrate models have similar effects to those we observed in T. castaneum, confirming that this beetle is potentially useful as an alternative model to screen for the epigenetic effect of drugs. T. castaneum also provides a valuable early warning system for transgenerational epigenetic risk factors that are difficult to detect in mammals.


Assuntos
Curcumina/toxicidade , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/toxicidade , Testes de Mutagenicidade , Tribolium/efeitos dos fármacos , Ácido Valproico/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hereditariedade , Sequenciamento de Nucleotídeos em Larga Escala , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Larva/efeitos dos fármacos , Larva/genética , Longevidade/efeitos dos fármacos , Masculino , Modelos Animais , Fenótipo , Reprodução/efeitos dos fármacos , Fatores de Tempo , Tribolium/genética
20.
Cell Death Differ ; 23(7): 1209-18, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26868908

RESUMO

Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostat-resistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 small-molecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/farmacologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Acetilação/efeitos dos fármacos , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Genoma Humano , Células HCT116 , Histonas/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , Regulação para Cima/efeitos dos fármacos , Vorinostat , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/genética , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
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