scholarly journals Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 344
Author(s):  
Bingbing Zhang ◽  
Zhu-Wei Ruan ◽  
Dongdong Luo ◽  
Yueyue Zhu ◽  
Tingbo Ding ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Inhibitory Activity ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Good Tolerance ◽  
Glycine Residue ◽  
Molecular Modeling Study ◽  
Rational Explanation ◽  
New Finding

Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole’s macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five–nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol. A molecular modeling study provided rational explanation and structural evidence for the enhanced inhibitory activity. This new finding will aid the design of novel potent HDAC inhibitors.

scholarly journals A Facile Ionic Liquid Promoted Synthesis, Cholinesterase Inhibitory Activity and Molecular Modeling Study of Novel Highly Functionalized Spiropyrrolidines

Molecules ◽  
2015 ◽  
Vol 20 (2) ◽  
pp. 2296-2309 ◽  
Author(s):  
Abdulrahman Almansour ◽  
Raju Kumar ◽  
Natarajan Arumugam ◽  
Alireza Basiri ◽  
Yalda Kia ◽  
...  
Keyword(s):  
Ionic Liquid ◽  
Molecular Modeling ◽  
Inhibitory Activity ◽  
Molecular Modeling Study ◽  
Cholinesterase Inhibitory Activity ◽  
Modeling Study

Molecular Modeling Study on Diazine Indole Acetic Acid Derivatives for CRTH2 Inhibitory Activity

2016 ◽  
Vol 19 (6) ◽  
pp. 444-460 ◽  
Author(s):  
Sathya Babu ◽  
Mottadi Rupa ◽  
Santhosh Kumar Nagarajan ◽  
Honglae Sohn ◽  
Thirumurthy Madhavan
Keyword(s):  
Acetic Acid ◽  
Molecular Modeling ◽  
Inhibitory Activity ◽  
Indole Acetic Acid ◽  
Molecular Modeling Study ◽  
Modeling Study

scholarly journals Cytoplasmic Interactions between the Glucocorticoid Receptor and HDAC2 Regulate Osteocalcin Expression in VPA-Treated MSCs

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 217 ◽  
Author(s):  
Marcella La Noce ◽  
Luigi Mele ◽  
Luigi Laino ◽  
Giovanni Iolascon ◽  
Gorizio Pieretti ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Severe Combined Immunodeficiency ◽  
Hdac Inhibitors ◽  
Stem Cell Differentiation ◽  
Mechanistic Explanation ◽  
Nonobese Diabetic

Epigenetic regulation has been considered an important mechanism for influencing stem cell differentiation. In particular, histone deacetylases (HDACs) have been shown to play a role in the osteoblast differentiation of mesenchymal stem cells (MSCs). In this study, the effect of the HDAC inhibitor, valproic acid (VPA), on bone formation in vivo by MSCs was determined. Surprisingly, VPA treatment, unlike other HDAC inhibitors, produced a well-organized lamellar bone tissue when MSCs–collagen sponge constructs were implanted subcutaneously into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, although a decrease of osteocalcin (OC) expression was observed. Consequently, we decided to investigate the molecular mechanisms by which VPA exerts such effects on MSCs. We identified the glucocorticoid receptor (GR) as being responsible for that downregulation, and suggested a correlation between GR and HDAC2 inhibition after VPA treatment, as evidenced by HDAC2 knockdown. Furthermore, using co-immunoprecipitation analysis, we showed for the first time in the cytoplasm, binding between GR and HDAC2. Additionally, chromatin immunoprecipitation (ChIP) assays confirmed the role of GR in OC downregulation, showing recruitment of GR to the nGRE element in the OC promoter. In conclusion, our results highlight the existence of a cross-talk between GR and HDAC2, providing a mechanistic explanation for the influence of the HDAC inhibitor (namely VPA) on osteogenic differentiation in MSCs. Our findings open new directions in targeted therapies, and offer new insights into the regulation of MSC fate determination.

Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases

2015 ◽  
Vol 75 (3) ◽  
pp. 593-600 ◽  
Author(s):  
Maartje C P Cleophas ◽  
Tania O Crişan ◽  
Heidi Lemmers ◽  
Helga Toenhake-Dijkstra ◽  
Gianluca Fossati ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Hdac Inhibitors ◽  
Class I ◽  
Acute Gout ◽  
Monosodium Urate ◽  
Healthy Donors ◽  
Anti Inflammatory

ObjectivesAcute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.MethodsFreshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.ResultsButyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.ConclusionsIn agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.

scholarly journals Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4991
Author(s):  
Jiangying Cao ◽  
Wei Zhao ◽  
Chunlong Zhao ◽  
Qian Liu ◽  
Shunda Li ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Inhibitory Activity ◽  
Hdac Inhibitor ◽  
Hdac Inhibitors ◽  
E3 Ubiquitin Ligase ◽  
Hydroxamic Acids ◽  
Dual Inhibitor ◽  
Apoptosis Protein ◽  
Inhibitory Activities ◽  
Potent Inhibitory Activity

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.

Abstract 238: Class I HDAC inhibition prevents Ncx1 upregulation by stabilizing an HDAC5-HDAC1/Sin3a Repressor Complex during cardiac hypertrophy.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sabina Wang ◽  
Lillianne G Harris ◽  
Santhosh Mani ◽  
Donald Menick
Keyword(s):  
Cardiac Hypertrophy ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Class I ◽  
Proximal Promoter ◽  
Hdac Inhibition ◽  
Repressor Complex

Cardiac hypertrophy is often associated with the activation of signaling pathways that perpetuate altered calcium efflux and influx. One gene that is upregulated and contributes to altered intracellular calcium concentrations and worsening contractility during cardiac hypertrophy is the Sodium Calcium Exchanger ( Ncx1 ). Molecular studies implicate histone deacetylases (HDACs) in possibly regulating the expression of this gene. Our recent work reveals that HDAC1, HDAC5 and Sin3a interact and are recruited to the Ncx1 promoter through the Nkx2.5 transcription factor. Interestingly, we observed greater associated/interaction of the HDAC1-HDAC5/Sin3a repressor complex upon broad HDAC inhibition. Taken together, we hypothesized that HDAC inhibition, stabilizes an HDAC1-HDAC5/Sin3a repressor complex during cardiac hypertrophy. We addressed this hypothesis by treating isolated adult cardiomyocytes with class specific HDAC inhibitors since HDAC1 is a Class I HDAC and HDAC5 is a Class IIa HDAC. Co-Immunoprecipitation (Co-IP) revealed a greater association of repressor complex molecules in the presence of Entinostat, a Class I HDAC inhibitor compared to both non-treated control and TSA, a broad HDAC inhibitor (n=3). These works show enhanced recruitment Sin3a (co-repressor) at the proximal promoter of NCX1 as demonstrated by Chromatin-Immunoprecipitation (ChIP) (n=3). To test whether these observations translated into in vivo models, we subjected mice to transaortic constriction (TAC) to induce hypertrophy. In this model, Co-IP revealed results that similar to our in vitro studies with greater immuno- detection of repressor complex component, Sin3a after immune-precipitation with HDAC1. Furthermore, our ChIP data showed a greater PCR product amplification of proximal Ncx1 promoter, from experimental groups that were subjected to Entinostat (n=3). Our cumulative data suggests that Class I HDAC inhibition stabilizes a repressor complex on the Ncx1 promoter that hinders hypertrophy- mediated Ncx1 upregulation. Class specific HDAC inhibition may be useful in the stabilization and repression of aberrantly expressed genes that contribute to poor clinical outcomes in cardiac hypertrophy.

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