Molecular Insights into Azumamide E Histone Deacetylases Inhibitory Activity

Maulucci, Nakia; Chini, Maria Giovanna; Micco, Simone Di; Izzo, Irene; Cafaro, Emiddio; Russo, A. Peter; Gallinari, Paola; Paolini, Chantal; Nardi, Maria Chiara; Casapullo, Agostino; Riccio, Raffaele; Bifulco, Giuseppe; Riccardis, Francesco De

doi:10.1021/ja0686256

Cited by 82 publications

(78 citation statements)

References 41 publications

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“…20 Like the aminobenzamides, cyclic peptides are reportedly class I-selective. [21][22][23] To date, no class I-selective compounds have been reported that demonstrate a high degree (Ͼ100ϫ) of selectivity between HDAC1 and HDAC2, which share nearly identical catalytic domains. Facilitated by the solution of the human HDAC8 crystal structure, 24 selective hydroxamate inhibitors of this distinct class I subfamily member have recently emerged.…”

Section: Hdaci Structural Classes and Selectivitymentioning

confidence: 99%

Protein Acetylation in the Cardiorenal Axis

Bush

McKinsey

2010

Circulation Research

116

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Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-tomesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs. (Circ Res. 2010; 106:272-284.)Key Words: acetylation Ⅲ histone deacetylase Ⅲ heart failure Ⅲ kidney failure Ⅲ fibrosis I t has been estimated that more than 5 million adults in the United States experience heart failure, and more than 20 million adults show signs of chronic kidney disease (CKD). 1,2 Of the patients with heart failure, Ϸ50% experience heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure, which is characterized at the cellular level by myocyte hypertrophy and activation of extracellular matrix (ECM)-producing fibroblasts. Current standard of care for systolic heart failure (eg, ACE inhibitors and ␤-blockers) provide little to no benefit to patients with HFpEF. 3 Likewise, therapy for CKD primarily focuses on lowering blood pressure through modulation of the renin-angiotensin system and maintaining blood glucose control, and this strategy only minimally slows the glomerular injury and insidious fibrotic mechanisms that culminate in end-stage renal disease. 4 The high rate of morbidity and mortality in patients with HFpEF and CKD underscores the urgent need for novel therapeutics. Histone deacetylases (HDACs) are emerging as key players in the pathogenesis of these diseases, suggesting unexpected potential for pharmacological inhibitors of HDACs in the treatment of disorders of the cardiorenal axis.Histone acetyltransferases (HATs) and HDACs act in an opposing manner to control the acetylation state of proteins. The most well characterized role for protein acetylation is in Original received September 15, 2009; revision received October 6, 2009; accepted October 27, 2009 the control of gene transcription. Acetylation of the -amino groups of lysine residues in nucleosomal histone tails by HATs is thought to relax chromatin structure by weakening the interaction of the positively charged histone tails with the negatively charged phosphate backbone of DNA, allowing access of transcriptional activators and gene induction. Deacetylation of histones by HDACs alters the electrostatic properties of chromatin in a manner that favors gene repression. Interestingly, a recent genome-wide chromatin immunoprecipitation analysis revealed preferen...

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Section: Hdaci Structural Classes and Selectivitymentioning

confidence: 99%

Protein Acetylation in the Cardiorenal Axis

Bush

McKinsey

2010

Circulation Research

116

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“…Because these large and diverse capping groups are believed to provide significant interactions with amino acid residues on the surface of the enzyme, members of the cyclic peptides or macrocyclic family of HDACi can possess a variety of ZBG (Fig. 8), including thiols (FK-228, largazole [75]), hydroxamic acids (compound 18 [76]), ketones (apicidin [77] (azumamide E [78]), and α-epoxy ketones (chlamydocin [79], trapoxin B [80]). …”

Section: Cyclic Peptides and Other Macrocyclesmentioning

confidence: 99%

“…For example, trapoxin B (an irreversible α-epoxy ketone) exhibits a 640-fold selectivity for HDAC1 vs HDAC6 with picomolar potency on HDAC1 (IC 50 =110 pM) [80]. In 2007, Maulucci et al [78] reported a series of cyclic tetrapetides, the azumamides, of which the most selective analog, azumamide E, displayed 100-fold selectivity for HDACs 1, 2, and 3 (50-100 nM) vs all other HDAC isoforms. Similarily, apicidin, another cyclic tetrapeptide possessing a ketone-based ZBG, showed preferential selectivity for HDACs 1, 2, 3, and 8 over all other HDAC isoforms [53].…”

Section: Cyclic Peptides and Other Macrocyclesmentioning

confidence: 99%

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

et al. 2013

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Lysine acetylation is an ancient, evolutionarily conserved, reversible post-translational modification. A multitude of diverse cellular functions are regulated by this dynamic modification, including energy and metabolism, protein folding, transcription, and translation. Gene expression can be manipulated through changes in histone acetylation status, and this process is controlled by the function of 2 opposing enzymes: histone acetyl transferases and histone deacetylases (HDACs). The zinc-dependent HDACs are a family of hydrolases that remove acetyl groups from lysines, and their function can be modulated by the action of small molecule ligands. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small molecule chemotypes. Structural biology has aided the development of potent, and in some cases highly isoformselective, inhibitors that have demonstrated utility in a number of neurological disease models. Continued development and characterization of highly optimized small molecule inhibitors of HDAC enzymes will help refine our understanding of their function and, optimistically, lead to novel therapeutic treatment alternatives for a host of neurological disorders.

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“…12 ■ RESULTS AND DISCUSSION Building Block Synthesis. For our synthesis of the β-amino acid building block, we chose a diastereoselective Ellman-type Mannich reaction to set the stereochemistry, as also previously reported by Ganesan and co-workers.…”

Section: ■ Introductionmentioning

confidence: 99%

“…g Determined by comparison of spectroscopic data of the fully elaborated Boc-protected β-amino acid with previously reported data. 12 Figure 2. X-ray crystal structure of the (2S,3S) precursor obtained by desilylation of the major product in entry 5 of Table 1.…”

Section: ■ Introductionmentioning

confidence: 99%

Total Synthesis and Full Histone Deacetylase Inhibitory Profiling of Azumamides A–E as Well as β²- epi-Azumamide E and β³-epi-Azumamide E

et al. 2013

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Cyclic tetrapeptide and depsipeptide natural products have proven useful as biological probes and drug candidates due to their potent activities as histone deacetylase (HDAC) inhibitors. Here, we present the syntheses of a class of cyclic tetrapeptide HDAC inhibitors, the azumamides, by a concise route in which the key step in preparation of the noncanonical disubstituted β-amino acid building block was an Ellman-type Mannich reaction. By tweaking the reaction conditions during this transformation, we gained access to the natural products as well as two epimeric homologues. Thus, the first total syntheses of azumamides B−D corroborated the originally assigned structures, and the synthetic efforts enabled the first full profiling of HDAC inhibitory properties of the entire selection of azumamides A−E. This revealed unexpected differences in the relative potencies within the class and showed that azumamides C and E are both potent inhibitors of HDAC10 and HDAC11.

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Molecular Insights into Azumamide E Histone Deacetylases Inhibitory Activity

Cited by 82 publications

References 41 publications

Protein Acetylation in the Cardiorenal Axis

Protein Acetylation in the Cardiorenal Axis

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

Total Synthesis and Full Histone Deacetylase Inhibitory Profiling of Azumamides A–E as Well as β²- epi-Azumamide E and β³-epi-Azumamide E

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Molecular Insights into Azumamide E Histone Deacetylases Inhibitory Activity

Cited by 82 publications

References 41 publications

Protein Acetylation in the Cardiorenal Axis

Protein Acetylation in the Cardiorenal Axis

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

Total Synthesis and Full Histone Deacetylase Inhibitory Profiling of Azumamides A–E as Well as β2- epi-Azumamide E and β3-epi-Azumamide E

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Product

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Total Synthesis and Full Histone Deacetylase Inhibitory Profiling of Azumamides A–E as Well as β²- epi-Azumamide E and β³-epi-Azumamide E