Modulation of the activity of histone acetyltransferases by long chain alkylidenemalonates (LoCAMs)

Milite, Ciro; Castellano, Sabrina; Benedetti, Rosaria; Tosco, Alessandra; Ciliberti, Carmen; Vicidomini, Caterina; Boully, Ludovic; Franci, Gianluigi; Altucci, Lucia; Mai, Antonello; Sbardella, Gianluca

doi:10.1016/j.bmc.2011.01.013

Cited by 30 publications

(21 citation statements)

References 77 publications

(92 reference statements)

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“…Efforts to isolate small-molecule activators using the basic backbone structure of anacardic acid are currently underway. In a recent study, pentadecylidenemalonate was prepared, which surprisingly showed mixed inhibitor/ activator properties towards HATs, as this chemical inhibited p300/CBP HAT activity and activated PCAF HAT activity [74,75]. Pentadecylidenemalonate/SPV106 could cross mammalian cell membranes and enhance histone H3 acetylation.…”

Section: Druggability Of Hat Domainsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Section: Druggability Of Hat Domainsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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“…Under chemically controlled conditions, these cells could be epigenetically reprogrammed to obtain functionally competent cardiovascular precursors with electrophysiology, gene expression, and microRNA profile similar to that of cardiomyocyte progenitors (11). Noteworthy, during the progress of these studies, we found that CMSC obtained from diabetic patients (D-CMSC) had a lower proliferation rate and failed to reprogram, suggesting the presence of a functional impairment (11,12).…”

mentioning

confidence: 98%

“…The proacetylation compound SPV106 has been described as an activator of the GCN5A/PCAF members of the GNAT family (20) and able to promote histone and nonhistone proteins acetylation (12). In our experiments, D-CMSC were cultured for ;6-8 days in the presence or absence of SPV106 at 25 mmol/L, a concentration established in a prior work (21).…”

Section: Epigenetic Enzymes Are Differentially Expressed Between Nd-cmentioning

confidence: 99%

The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

et al. 2014

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This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-a general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients.In recent decades, in association with the progressive increase of the average population age in western countries, type 2

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“…11 However, besides being an expensive reagent, DMP is potentially explosive 12 and therefore not suitable for multigram scale. On the other hand, among the various oxidants for alcohols , the oxidation with with 2,2,6,6-tetramethylpiperidine-N-oxy (TEMPO) results very appealing since it is a non-metallic catalyst and, foremost, it is environmentally friendly and economical.…”

Section: Resultsmentioning

confidence: 99%

Straightforward, metal-free, and stereoselective synthesis of 9-oxo- and 10-hydroxy-2(E)-decenoic acids, important components of honeybee (Apis mellifera) secretions

et al. 2012

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Abstract10-hydroxy-2E-decenoic (10-HDA) and 9-oxo-2E-decenoic (9-ODA) acids, two components identified in honeybees secretions, have both received considerable recent interest due to their involvement in caste switch and maintenance. Herein we report for the first time a metal-free, gram scale, and stereoselective synthesis of these honeybee secretion components by TEMPO catalyzed oxidation of readily available alcohols and subsequent Doebner-Knoevenagel reaction between the resulting aldehydes and malonic acid. Mechanistic investigations undertaken highlighted the crucial role of the Doebner-Knoevenagel reaction in the high yielding and selective preparation of the α,β-unsaturated acids 10-HDA and 9-ODA.The combination of inexpensive and environmental friendly reagents with simple synthetic procedures render this approach a valuable green strategy for the gram scale preparation of these biologically relevant natural molecules. Graphical abstract

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Modulation of the activity of histone acetyltransferases by long chain alkylidenemalonates (LoCAMs)

Cited by 30 publications

References 77 publications

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

Straightforward, metal-free, and stereoselective synthesis of 9-oxo- and 10-hydroxy-2(E)-decenoic acids, important components of honeybee (Apis mellifera) secretions

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