RESUMO
Clinical treatment of candidiasis has suffered from increasingly severe drug resistance and limited efficacy. Thus, novel strategies to deal with drug resistance are highly desired to develop effective therapeutic agents. Herein, dual inhibition of heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) was validated as a new strategy to potentiate efficacy of fluconazole against resistant Candida albicans infections. The first generation of Hsp90/HDAC dual inhibitors were designed as synergistic enhancers to treat azoles-resistant candidiasis. In particular, compound J5 exhibited fungal-selective inhibitory effects on Hsp90 and HDACs, leading to low toxicity and excellent in vitro (FICI = 0.266) and in vivo synergistic antifungal potency to treat fluconazole resistant candidiasis. Antifungal-mechanistic investigation revealed that compound J5 suppressed important virulence factors and down-regulated expression of resistance-associated genes. Therefore, Hsp90/HDAC dual inhibitors represent a new strategy for the development of novel antifungal therapeutics to combat azole-resistant candidiasis.
Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Animais , Antifúngicos/síntese química , Antifúngicos/química , Azóis/síntese química , Azóis/química , Relação Dose-Resposta a Droga , Farmacorresistência Fúngica/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Invasive fungal infections remain a challenge due to lack of effective antifungal agents and serious drug resistance. Discovery of antifungal agents with novel antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual inhibitors with potent activity against resistant Candida albicans infections. To better understand the antifungal spectrum and synergistic mechanism, herein new CYP51/HDAC dual inhibitors were designed which showed potent in vitro and in vivo antifungal activity against C. neoformans and C. tropicalis infections. Antifungal mechanism studies revealed that the CYP51/HDAC dual inhibitors acted by inhibiting various virulence factors of C. tropicalis and C. neoformans and down-regulating resistance-associated genes. This study highlights the potential of CYP51/HDAC dual inhibitors as a promising strategy for the discovery of novel broad-spectrum antifungal agents.
Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Antifúngicos/farmacologia , Candidíase Cutânea/tratamento farmacológico , Criptococose/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de 14-alfa Desmetilase/síntese química , Inibidores de 14-alfa Desmetilase/química , Antifúngicos/síntese química , Antifúngicos/química , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/metabolismo , Candidíase Cutânea/metabolismo , Criptococose/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/metabolismo , Família 51 do Citocromo P450/antagonistas & inibidores , Família 51 do Citocromo P450/metabolismo , Relação Dose-Resposta a Droga , Farmacorresistência Fúngica/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aß25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Cumáricos/uso terapêutico , Desacetilase 6 de Histona/antagonistas & inibidores , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Triptaminas/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Animais , Domínio Catalítico , Linhagem Celular Transformada , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/metabolismo , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Fatores Imunológicos/síntese química , Fatores Imunológicos/metabolismo , Masculino , Melatonina/análogos & derivados , Melatonina/metabolismo , Melatonina/uso terapêutico , Camundongos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/metabolismoRESUMO
Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Sirtuína 1/metabolismo , Sirtuína 2/metabolismo , Sirtuína 3/metabolismo , Relação Estrutura-AtividadeRESUMO
Due to the evolution and development of antifungal drug resistance, limited efficacy of existing drugs has led to high mortality in patients with serious fungal infections. To develop novel antifungal therapeutic strategies, herein a series of carboline fungal histone deacetylase (HDAC) inhibitors were designed and synthesized, which had potent synergistic effects with fluconazole against resistant Candida albicans infection. In particular, compound D12 showed excellent in vitro and in vivo synergistic antifungal efficacy with fluconazole to treat azole-resistant candidiasis. It cooperated with fluconazole in reducing the virulence of C. albicans by blocking morphological mutual transformation and inhibiting biofilm formation. Mechanism studies revealed that the reversion of drug resistance was due to downregulation of the expression of the azole target gene ERG11 and efflux gene CDR1. Taken together, fungal HDAC inhibitor D12 offered a promising lead compound for combinational treatment of azole-resistant candidiasis.
Assuntos
Azóis/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Carbolinas/síntese química , Carbolinas/uso terapêutico , Farmacorresistência Fúngica/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Biofilmes/efeitos dos fármacos , Candida albicans/enzimologia , Candidíase/microbiologia , Carbolinas/toxicidade , Quimioterapia Combinada , Feminino , Fluconazol/farmacologia , Proteínas Fúngicas/efeitos dos fármacos , Fungos/efeitos dos fármacos , Fungos/enzimologia , Inibidores de Histona Desacetilases/toxicidade , Humanos , Fígado/patologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade MicrobianaRESUMO
Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.
Assuntos
Antraquinonas/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Antraquinonas/síntese química , Antraquinonas/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reparo do DNA , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 - 9.3 µM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 - 28.2 µM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 - 104.2 µM) and human fibroblasts (HS27) (CC50 - 105.0 µM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
Assuntos
Inibidores de Histona Desacetilases/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Tiazolidinedionas/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacologiaRESUMO
Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC50 = 2.7 nM and IC50 = 3.1 nM), HDAC2 (IC50 = 4.2 nM and IC50 = 3.6 nM) and HDAC8 (IC50 = 3.6 nM and IC50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Histona Desacetilases/farmacologia , Indazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Indazóis/síntese química , Indazóis/química , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-AtividadeRESUMO
Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aß-aggregation as well as significantly disrupted Aß-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aß-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.
Assuntos
Acridinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Acetilcolinesterase/metabolismo , Acridinas/síntese química , Acridinas/química , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.
Assuntos
Desenho de Fármacos , Inibidores de Histona Desacetilases/síntese química , Ácidos Hidroxâmicos/síntese química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Quinazolinonas/síntese química , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Células HEK293 , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Estrutura Terciária de Proteína , Quinazolinonas/farmacologia , RatosRESUMO
The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
Assuntos
Benzamidas/metabolismo , Ácido Glutâmico/química , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Transferência Ressonante de Energia de Fluorescência , Células HeLa , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Peixe-ZebraRESUMO
Human histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of α-tubulin, making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available, providing avenues for structure-based drug design campaign. Here, in our continuous effort to identify potentially selective HDAC6 inhibitors, structure-based virtual screening of â¼72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated ΔG <â¯-10â¯kcal/mol were manually inspected for binding mode orientation. Furthermore, the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment, displayed potential selectivity for HDAC6 over HDAC7, and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software, to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions, and the root-mean-square deviation (RMSD), radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity.
Assuntos
Ácidos Carboxílicos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Biocatálise , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomycetes origin, such as phenolics, polyketides, tetrapeptide, terpenoids, alkaloids, and hydoxamic acid, have been reported to show potential HDAC-inhibitory activity. Several HDACi of natural and dietary origin are butein, protocatechuic aldehyde, kaempferol (grapes, green tea, tomatoes, potatoes, and onions), resveratrol (grapes, red wine, blueberries and peanuts), sinapinic acid (wine and vinegar), diallyl disulfide (garlic), and zerumbone (ginger). HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells. This review summarizes the HDACs classification, their aberrant expression in cancerous tissue, structures, sources, and the anticancer mechanisms of HDACi, as well as HDACi that are either FDA-approved or under clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Histonas/metabolismo , Neoplasias/tratamento farmacológico , Acetilação , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/síntese química , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/classificação , Histona Desacetilases/genética , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Especificidade por SubstratoRESUMO
This work demonstrated the high efficiency of a sub-milligram-synthesis based medicinal chemistry method. Totally 72 compounds, consisting a tri-substituted pyrrolidine core, were prepared. Around 0.1mg of each compound was solid-phase synthesized. Based on the additive property of UV absorptions of unconjugated chromophores of a molecule, these compounds were quantified by UV measurement. A hit, whose IC50 value was 1.2µM in HDAC11 inhibition assays, highlights the applicability of the approach reported here in future optimization works.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Animais , Histona Desacetilases/química , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Células Sf9 , Técnicas de Síntese em Fase Sólida , Espectrofotometria Ultravioleta , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition. METHODS & RESULTS: Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3. CONCLUSION: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Ácidos Isonicotínicos/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Pró-Fármacos/farmacologia , Pirimidinas/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Isonicotínicos/síntese química , Ácidos Isonicotínicos/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.
Assuntos
Química Farmacêutica/métodos , Inibidores de Histona Desacetilases/química , Peptídeos Cíclicos/química , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/síntese química , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ligação Proteica , Conformação ProteicaRESUMO
A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.
Assuntos
DNA Topoisomerases Tipo II/metabolismo , Inibidores de Histona Desacetilases , Histona Desacetilases/metabolismo , Fenilenodiaminas/farmacologia , Podofilotoxina/análogos & derivados , Inibidores da Topoisomerase II , DNA Topoisomerases Tipo II/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/toxicidade , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Podofilotoxina/síntese química , Podofilotoxina/química , Podofilotoxina/farmacologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , VorinostatRESUMO
We report the design, synthesis, and biological evaluation of a new series of HDAC1 inhibitors using click chemistry. Compound 17 bearing a phenyl ring at meta-position was identified to show much better selectivity for HDAC1 over HDAC7 than SAHA. The compond 17 also showed better in vitro anticancer activities against several cancer cell lines than that of SAHA. This work could serve as a foundation for further exploration of selective HDAC inhibitors using the compound 17 molecular scaffold.
Assuntos
Desenho de Fármacos , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Química Click , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/toxicidade , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade , VorinostatRESUMO
A series of novel benzamides derivatives was designed and synthesized as HDAC inhibitors. Exploration of the structure-activity relationships resulted in compounds that are potent in vitro. In addition, the best compound 1a exhibited an acceptable pharmacokinetic profile with bioavailability in rat of 81% and could be considered as a candidate compound for further development.
Assuntos
Benzamidas/química , Benzamidas/síntese química , Desenho de Fármacos , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/química , Pirimidinas/síntese química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Meia-Vida , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/metabolismo , Humanos , Células MCF-7 , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Ratos , Relação Estrutura-AtividadeRESUMO
As part of an effort to identify novel selective modulators of sirtuins, we synthesized and tested several isosteres and constrained analogues of nicotinamide. Biological data suggest that compound 2 is selective for Sirt3 over Sirt1 and Sirt2.