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1.
Histone deacetylases (HDACs) are important enzymes in epigenetic regulation and are therapeutic targets for cancer. Most zinc‐dependent HDACs induce proliferation, dedifferentiation, and anti‐apoptotic effects in cancer cells. We designed and synthesized a new series of pyridone‐based HDAC inhibitors that have a pyridone ring in the core structure and a conjugated system with an olefin connecting the hydroxamic acid moiety. Consequently, most of the selected pyridone‐based HDAC inhibitors showed similar or higher inhibition profiles in addition to remarkable metabolic stability against hydrolysis relative to the corresponding lactam‐based HDAC inhibitors. Furthermore, the selectivity of the novel pyridine‐based compounds was evaluated across all of the HDAC isoforms. One of these compounds, (E)‐N‐hydroxy‐3‐{1‐[3‐(naphthalen‐2‐yl)propyl]‐2‐oxo‐1,2‐dihydropyridin‐3‐yl}acrylamide, exhibited the highest level of HDAC inhibition (IC50=0.07 μM ), highly selective inhibition of class I HDAC1 and class II HDAC6 enzymes, metabolic stability in mouse liver microsomal studies, and effective growth inhibition of various cancer cell lines. Docking studies indicated that a long alkyl linker and bulky hydrophobic cap groups affect in vitro activities. Overall, the findings reported herein regarding pyridone‐based HDAC inhibitors can be used to guide future research efforts to develop new and effective anticancer therapeutics.  相似文献   

2.
A novel series of hybrids was designed and synthesized by combining key elements from farnesylthiosalicylic acid (FTS) and hydroxamic acid. Several 3,7,11‐trimethyldodeca‐2,6,10‐trien‐1‐yl) thio)benzamide derivatives, particularly those with branched and linear aliphatic linkers between the hydroxamic zinc binding group (ZBG) and the benzamide core, not only displayed significant antitumor activities against six human cancer cells but also exhibited histone deacetylase (HDAC) inhibitory effects in vitro. Among them, N‐(4‐(hydroxyamino)‐4‐oxobutyl)‐2‐(((2E,6E)‐3,7,11‐trimethyldodeca‐2,6, 10‐trien‐1‐yl)thio)benzamide ( 8 d ) was the most potent, with IC50 values of 4.9–7.6 μM ; these activities are eight‐ to sixteen‐fold more potent than FTS and comparable to that of suberoylanilide hydroxamic acid (SAHA). Derivative 8 d induced cell cycle arrest in the G0/G1 phase, inhibited the acetylation of histone H3 and α‐tubulin, and blocked Ras‐related signaling pathways in a dose‐dependent manner. The improved tumor growth inhibition and cell‐cycle arrest in vitro might result from the dual inhibition. These findings suggest dual inhibitors of Ras‐related signaling pathway and HDAC hold promise as therapeutic agents for the treatment of cancer.  相似文献   

3.
Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50=40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50=42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat ( 1 ) toward this particular HDAC isoform.  相似文献   

4.
Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide ( 5 b ) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6 – 8 , 9 b , as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide ( 9 b ) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates ( 9 a , 9 c – f , and 11 a – f ) and 2′-aminoanilides ( 10 a – f and 12 a – f ), related to 9 b , to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC50: 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2′-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC50HDAC3=0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e , 11 c , and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b , 11 c , 10 b , 10 e , and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level.  相似文献   

5.
A series of 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines ( 7 – 15 ) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC‐inhibitory and antiproliferative activities than 3‐(1‐benzenesulfonyl‐1H‐indol‐5‐yl)‐N‐hydroxyacrylamide ( 6 ), as reported in a previous study. Among these compounds, 3‐[1‐(4‐methoxybenzenesulfonyl)‐2,3‐dihydro‐1H‐indol‐5‐yl]‐N‐hydroxyacrylamide ( 9 ) showed a two‐ to tenfold increase in activity compared to SAHA ( 1 ) in the suppression of lipopolysaccharide‐induced cytokine production. Compound 9 also caused a marked reduction in carrageenan‐induced acute inflammation in a rat model. Taken together, these data indicated that 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti‐inflammatory activity.  相似文献   

6.
The inhibitors of histone deacetylases (HDACs) have drawn a great deal of attention due to their promising potential as small‐molecule therapeutics for the treatment of cancer. By means of virtual screening with docking simulations under consideration of the effects of ligand solvation, we were able to identify six novel HDAC inhibitors with IC50 values ranging from 1 to 100 μM . These newly identified inhibitors are structurally diverse and have various chelating groups for the active site zinc ion, including N‐[1,3,4]thiadiazol‐2‐yl sulfonamide, N‐thiazol‐2‐yl sulfonamide, and hydroxamic acid moieties. The former two groups are included in many drugs in current clinical use and have not yet been reported as HDAC inhibitors. Therefore, they can be considered as new inhibitor scaffolds for the development of anticancer drugs by structure–activity relationship studies to improve the inhibitory activities against HDACs. Interactions with the HDAC1 active site residues responsible for stabilizing these new inhibitors are addressed in detail.  相似文献   

7.
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC50 values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC50=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC50=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC50=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds.  相似文献   

8.
Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in‐house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in‐house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC50 values ranging from ~300 nM to ~15 μM , by testing only 133 compounds from a database of ~125 000 compounds. Structure–activity relationship studies and X‐ray co‐crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC50 value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.  相似文献   

9.
In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC50=13.3±1.5 μm , HDAC1 IC50=3.38±0.14 μm , HDAC6 IC50=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC50 value of 3.7±0.5 μm .  相似文献   

10.
Carbamates are a well‐established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta‐substituted phenolic N‐alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3‐(oxazol‐2yl)phenyl cyclohexylcarbamate ( 2 a ), inhibited FAAH with a sub‐nanomolar IC50 value (IC50=0.74 nM ). Additionally, we developed and validated three‐dimensional quantitative structure–activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D‐QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D‐QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R2PRED) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.  相似文献   

11.
Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone‐dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase–sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub‐nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole‐derived sulfamates and a vorozole‐based sulfamate were designed and biologically evaluated in JEG‐3 cells to reveal structure–activity relationships. Amongst achiral and racemic compounds, 2‐bromo‐4‐(2‐(4‐cyanophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC50=0.87 nM ; STS: IC50=593 nM ). The enantiomers of the phenolic precursor to this compound were separated by chiral HPLC and their absolute configuration determined by X‐ray crystallography. Following conversion to their corresponding sulfamates, the S‐(+)‐enantiomer was found to inhibit aromatase and sulfatase most potently (aromatase: IC50=0.52 nM ; STS: IC50=280 nM ). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.  相似文献   

12.
We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.  相似文献   

13.
A series of small‐molecule histone deacetylase (HDAC) inhibitors, which feature zinc binding groups derived from cysteine, were synthesized. These inhibitors were tested against multiple HDAC isoforms, and the most potent, compound 10 , was determined to have IC50 values below 1 μM . The compounds were also tested in a cellular assay of oxidative stress‐induced neurodegeneration. Many of the inhibitors gave near‐complete protection against cell death at 10 μM without the neurotoxicity seen with hydroxamic acid‐based inhibitors, and were far more neuroprotective than HDAC inhibitors currently in clinical trials. Both enantiomers of cysteine were used in the synthesis of a variety of novel zinc‐binding groups (ZBGs). Derivatives of L ‐cysteine were active in the HDAC inhibition assays, while the derivatives of D ‐cysteine were inactive. Notably, the finding that both the D ‐ and L ‐cysteine derivatives were active in the neuroprotection assays suggests that multiple mechanisms are working to protect the neurons from cell death. Molecular modeling was employed to investigate the differences in inhibitory activity between the HDAC inhibitors generated from the two enantiomeric forms of cysteine.  相似文献   

14.
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 ).  相似文献   

15.
Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N‐cinnamoylated quinacrine surrogates, 9‐(N‐cinnamoylaminobutyl)‐amino‐6‐chloro‐2‐methoxyacridines, is reported. The compounds were found to be highly potent against both blood‐stage P. falciparum, chloroquine‐sensitive 3D7 (IC50=17.0–39.0 nM ) and chloroquine‐resistant W2 and Dd2 strains (IC50=3.2–41.2 and 27.1–131.0 nM , respectively), and liver‐stage P. berghei (IC50=1.6–4.9 μM ) parasites. These findings bring new hope for the possible future “rise of a fallen angel” in antimalarial chemotherapy, with a potential resurgence of quinacrine‐related compounds as dual‐stage antimalarial leads.  相似文献   

16.
Tetrahydroisoquinoline (THIQ)‐based “chimeric” microtubule disruptors were optimised through modification of the N‐benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15 : GI50 20 nM in DU‐145). The broad anticancer activity of these novel structures was confirmed in the NCI 60‐cell line assay, with 12 e , f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15 , for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM , close to that of the clinical drug combretastatin A‐4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50=1.6 μM ). Compound 12 f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.  相似文献   

17.
4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate and its ortho‐halogenated (F, Cl, Br) derivatives are first‐generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para‐cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG‐3 cell preparation of 0.2 and 2.5 nM , respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nM in the same assay.  相似文献   

18.
In the present study, a novel series of 11 urushiol-based hydroxamic acid histone deacetylase (HDAC) inhibitors was designed, synthesized, and biologically evaluated. Compounds 1 – 11 exhibited good to excellent inhibitory activities against HDAC1/2/3 (IC50: 42.09–240.17 nM) and HDAC8 (IC50: 16.11–41.15 nM) in vitro, with negligible activity against HDAC6 (>1409.59 nM). Considering HDAC8, docking experiments revealed some important features contributing to inhibitory activity. According to Western blot analysis, select compounds could notably enhance the acetylation of histone H3 and SMC3 but not-tubulin, indicating their privileged structure is appropriate for targeting class I HDACs. Furthermore, antiproliferation assays revealed that six compounds exerted greater in vitro antiproliferative activity against four human cancer cell lines (A2780, HT-29, MDA-MB-231, and HepG2, with IC50 values ranging from 2.31–5.13 μM) than suberoylanilide hydroxamic acid; administration of these compounds induced marked apoptosis in MDA-MB-231 cells, with cell cycle arrest in the G2/M phase. Collectively, specific synthesized compounds could be further optimized and biologically explored as antitumor agents.  相似文献   

19.
A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at <100 nM in the HDAC inhibition assays, sub‐micromolar IC50 values in tests against three tumor cell lines, and remarkable stability in human and mouse microsomes was observed. Three representative compounds were selected for further characterization and submitted to a selectivity profile against a series of class I and class II HDACs as well as to preliminary in vivo pharmacokinetic (PK) experiments. Despite their high microsomal stability, the compounds showed medium‐to‐high clearance rates in in vivo PK studies as well as in rat and human hepatocytes, indicating that a major metabolic pathway is catalyzed by non‐microsomal enzymes.  相似文献   

20.
We describe the 3D‐QSAR‐assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D‐QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC50 values toward Aurora kinase A ranging from 33 nM to 10.5 μM . The best 3D‐QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r2CV=0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R2pred=0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent‐exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC50=43 nM ; HCT‐116 IC50=400 nM ) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC50=25 nM ; HCT‐116 IC50=23 nM ). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24 , and holds potential for further development.  相似文献   

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