ABSTRACT
Alzheimer's disease (AD) and cancer are among the most devastating diseases of the 21st century. Although the clinical manifestations are different and the cellular mechanisms underlying the pathologies are opposite, there are different classes of molecules that are effective in both diseases, such as quinone-based compounds and histone deacetylase inhibitors (HDACIs). Herein, we investigate the biological effects of a series of compounds built to exploit the beneficial effects of quinones and histone deacetylase inhibition (compounds 1-8). Among the different compounds, compound 6 turned out to be a potent cytotoxic agent in SH-SY5Y cancer cell line, with a half maximal inhibitory concentration (IC50) value lower than vorinostat and a pro-apoptotic activity. On the other hand, compound 8 was nontoxic up to the concentration of 100 µM and was highly effective in stimulating the proliferation of neural precursor cells (NPCs), as well as inducing differentiation into neurons, at low micromolar concentrations. In particular, it was able to induce NPC differentiation solely towards a neuronal-specific phenotype, without affecting glial cells commitment.
ABSTRACT
Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3ß (GSK-3ß). The synthesized compounds are highly potent GSK-3ß, HDAC2, and HDAC6 inhibitors with IC50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 µM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.
Subject(s)
Alzheimer Disease , Glycogen Synthase Kinase 3 beta , Histone Deacetylase Inhibitors , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Humans , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/metabolism , Animals , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , tau Proteins/metabolism , Histone Deacetylases/metabolism , Phosphorylation/drug effects , Acetylation , Histone Deacetylase 2/metabolism , Histone Deacetylase 2/antagonists & inhibitorsABSTRACT
Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 µM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 µM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.
Subject(s)
Glioblastoma , Prostatic Neoplasms , Humans , Male , Monoamine Oxidase , Polyamines/pharmacology , Monoamine Oxidase Inhibitors/pharmacologyABSTRACT
Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine kinase and an attractive therapeutic target for Alzheimer's disease. Based on proteolysis-targeting chimera (PROTAC) technology, a small set of novel GSK-3ß degraders was designed and synthesized by linking two different GSK-3ß inhibitors, SB-216763 and tideglusib, to pomalidomide, as E3 recruiting element, through linkers of different lengths. Compound 1 emerged as the most effective PROTAC being nontoxic up to 20 µM to neuronal cells and already able to degrade GSK-3ß starting from 0.5 µM in a dose-dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by Aß25-35 peptide and CuSO4 in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging features, PROTAC 1 may serve as a starting point to develop new GSK-3ß degraders as potential therapeutic agents.
Subject(s)
Alzheimer Disease , Neuroblastoma , Humans , Alzheimer Disease/drug therapy , Glycogen Synthase Kinase 3 beta , Protein Serine-Threonine Kinases , PhosphorylationABSTRACT
Targeted protein degradation (TPD) is emerging as one of the most innovative strategies to tackle infectious diseases. Particularly, proteolysis-targeting chimera (PROTAC)-mediated protein degradation may offer several benefits over classical anti-infective small-molecule drugs. Because of their peculiar and catalytic mechanism of action, anti-infective PROTACs might be advantageous in terms of efficacy, toxicity, and selectivity. Importantly, PROTACs may also overcome the emergence of antimicrobial resistance. Furthermore, anti-infective PROTACs might have the potential to (i) modulate "undruggable" targets, (ii) "recycle" inhibitors from classical drug discovery approaches, and (iii) open new scenarios for combination therapies. Here, we try to address these points by discussing selected case studies of antiviral PROTACs and the first-in-class antibacterial PROTACs. Finally, we discuss how the field of PROTAC-mediated TPD might be exploited in parasitic diseases. Since no antiparasitic PROTAC has been reported yet, we also describe the parasite proteasome system. While in its infancy and with many challenges ahead, we hope that PROTAC-mediated protein degradation for infectious diseases may lead to the development of next-generation anti-infective drugs.
ABSTRACT
Natural polyamines (PAs) are key players in cellular homeostasis by regulating cell growth and proliferation. Several observations highlight that PAs are also implicated in pathways regulating cell death. Indeed, the PA accumulation cytotoxic effect, maximized with the use of bovine serum amine oxidase (BSAO) enzyme, represents a valuable strategy against tumor progression. In the present study, along with the design, synthesis, and biological evaluation of a series of new spermine (Spm) analogues (1-23), a mixed structure-based (SB) and ligand-based (LB) protocol was applied. Binding modes of BSAO-PA modeled complexes led to clarify electrostatic and steric features likely affecting the BSAO-PA biochemical kinetics. LB and SB three-dimensional quantitative structure-activity relationship (Py-CoMFA and Py-ComBinE) models were developed by means of the 3d-qsar.com portal, and their analysis represents a strong basis for future design and synthesis of PA BSAO substrates for potential application in oxidative stress-induced chemotherapy.
Subject(s)
Antineoplastic Agents , Quantitative Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Ligands , Molecular Docking Simulation , Monoamine Oxidase/metabolism , Polyamines/metabolism , Polyamines/pharmacology , Spermine/pharmacology , Spermine/therapeutic useABSTRACT
Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To fully harness the potential of this technology, a growing paradigm toward enriching PROTACs with other therapeutic modalities has been proposed. Could researchers successfully combine two modalities to yield multifunctional PROTACs with an expanded profile? In this Perspective, we try to answer this question. We discuss how this possibility encompasses different approaches, leading to multitarget PROTACs, light-controllable PROTACs, PROTAC conjugates, and macrocycle- and oligonucleotide-based PROTACs. This possibility promises to further enhance PROTAC efficacy and selectivity, minimize side effects, and hit undruggable targets. While PROTACs have reached the clinical investigation stage, additional steps must be taken toward the translational development of multifunctional PROTACs. A deeper and detailed understanding of the most critical challenges is required to fully exploit these opportunities and decisively enrich the PROTAC toolbox.
Subject(s)
Ubiquitin-Protein Ligases , Drug Discovery , Proteolysis , Ubiquitin-Protein Ligases/metabolismABSTRACT
Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products.
Subject(s)
Biological Products , Catalysis , Biological Products/chemistry , Chemistry, PharmaceuticalABSTRACT
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3ß or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3ß/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3ß and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3ß/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.
Subject(s)
Cell Survival/drug effects , Epileptic Syndromes/drug therapy , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Histone Deacetylase Inhibitors , Neurons/drug effects , Spasms, Infantile/drug therapy , Animals , Cell Line , Hippocampus/drug effects , Hippocampus/pathology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/pathologyABSTRACT
Alzheimer's disease (AD), like other multifactorial diseases, is the result of a systemic breakdown of different physiological networks. As result, several lines of evidence suggest that it could be more efficiently tackled by molecules directed toward different dysregulated biochemical targets or pathways. In this context, the selection of targets to which the new molecules will be directed is crucial. For years, the design of such multitarget-directed ligands (MTDLs) has been based on the selection of main targets involved in the "cholinergic" and the "ß-amyloid" hypothesis. Recently, there have been some reports on MTDLs targeting the glycogen synthase kinase 3ß (GSK-3ß) enzyme, due to its appealing properties. Indeed, this enzyme is involved in tau hyperphosphorylation, controls a multitude of CNS-specific signaling pathways, and establishes strict connections with several factors implicated in AD pathogenesis. In the present Miniperspective, we will discuss the reasons behind the development of GSK-3ß-directed MTDLs and highlight some of the recent efforts to obtain these new classes of MTDLs as potential disease-modifying agents.
Subject(s)
Alzheimer Disease/drug therapy , Drug Discovery , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta/chemistry , Humans , PhosphorylationABSTRACT
Drugs targeting human topoisomerase II (topoII) are used in clinical practice since decades. Nevertheless, there is an urgent need for new and safer topoII inhibitors due to the emergence of secondary malignancies and the appearance of resistance mechanisms upon treatment with topoII-targeted anticancer drugs. In the present investigation, we report the discovery of a new topoII inhibitor, whose design was based on the structure of the natural product trypthantrin, a natural alkaloid containing a basic indoloquinazoline moiety. This new topoII inhibitor, here numbered compound 5, is found to inhibit topoII with an IC50 of 26.6 ± 4.7 µM. Notably, compound 5 is more potent than the template compound trypthantrin, and even than the widely used topoII-targeted clinical drug etoposide. In addition, compound 5 also exhibits high water solubility, and a promising antiproliferative activity on different tumor cell lines such as acute leukemia, colon, and breast cancer. In light of these results, compound 5 represents a promising lead for developing new topoII inhibitors as anti-cancer therapeutic agents.
Subject(s)
Antineoplastic Agents/pharmacology , DNA Topoisomerases, Type II/metabolism , Drug Discovery , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Tumor Cells, CulturedABSTRACT
PURPOSE OF REVIEW: Traumatic brain injury (TBI) is one of the leading causes of death in the developed world. Despite advances at the bedside, pharmacological interventions have yet to be successful likely because of the need for a better understanding of disease mechanisms as potential targets for intervention. Recent evidence implicates a family of enzymes, namely transglutaminases, in the pathological mechanisms of TBI. RECENT FINDINGS: Transglutaminases are multifunctional, calcium-dependent enzymes that are significantly upregulated in TBI. They are known for their transamidase activity that consists of the covalent crosslinking of glutamines and lysines. Recent data support their ability to aminylate proteins with primary amines such as polyamines or monoamines like serotonin and histamine and to regulate gene transcription. SUMMARY: In this review, we will discuss data that support a role for transglutaminases, in particular transglutaminase 2, in mitochondrial damage, excitotoxicity and inflammation and their relationship to the pathobiology of TBI. We will review past evidence and outline the need for new experiments that could clarify the role of these enzymes in cell injury and death associated with traumatic brain injury.
Subject(s)
Brain Injuries, Traumatic , Cell Death , Inflammation , Nerve Regeneration , Neurons , Transglutaminases/metabolism , Animals , Brain Injuries, Traumatic/immunology , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/pathology , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Neurons/immunology , Neurons/metabolism , Neurons/pathologyABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00507.].
ABSTRACT
Cancer represents one of the leading causes of death worldwide. Progresses in treatment of cancer have continued at a rapid pace. However, undesirable side effects and drug resistance remain major challenges for therapeutic success. Natural products represent a valuable starting point to develop new anticancer strategies. Polyphenols, well-known as antioxidant, exert anticancer effects through the modulation of multiple pathways and mechanisms. Oat (Avena sativa L., Poaceae) is a unique source of avenanthramides (AVAs), a group of polyphenolic alkaloids, considered as its signature compounds. The present review aims to offer a comprehensive and critical perspective on the chemopreventive and chemotherapeutic potential of AVAs. AVAs prevent cancer mainly by blocking reactive species. Moreover, they exhibit potential therapeutic activity through the modulation of different pathways including the activation of apoptosis and senescence, the block of cell proliferation, and the inhibition of epithelial mesenchymal transition and metastatization. AVAs are promising chemopreventive and anticancer phytochemicals, which need further clinical trials and toxicological studies to define their efficacy in preventing and reducing the burden of cancer diseases.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Avena/chemistry , Neoplasms/drug therapy , ortho-Aminobenzoates/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Epithelial-Mesenchymal Transition/drug effects , Humans , Neoplasms/metabolism , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Signal Transduction/drug effects , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacologyABSTRACT
The self-assembly of amyloid peptides (Aß), in particular Aß1-42, into oligomers and fibrils is one of the main pathological events related to Alzheimer's disease. Recent studies have demonstrated the ability of carbon monoxide-releasing molecules (CORMs) to protect neurons and astrocytes from Aß1-42 toxicity. In fact, CORMs are able to carry and release controlled levels of CO and are known to exert a wide range of anti-inflammatory and anti-apoptotic activities at physiologically relevant concentrations. In order to investigate the direct effects of CORMs on Aß1-42, we studied the reactivity of CORM-2 and CORM-3 with Aß1-42 in vitro and the potential inhibition of its aggregation by mass spectrometry (MS), as well as fluorescence and circular dichroism spectroscopies. The application of an electrospray ionization-MS (ESI-MS) method allowed the detection of stable Aß1-42/CORMs adducts, involving the addition of the Ru(CO)2 portion of CORMs at histidine residues on the Aß1-42 skeleton. Moreover, CORMs showed anti-aggregating properties through formation of stable adducts with Aß1-42 as demonstrated by a thioflavin T fluorescence assay and MS analysis. As further proof, comparison of the CD spectra of Aß1-42 recorded in the absence and in the presence of CORM-3 at a 1:1 molar ratio showed the ability of CORM-3 to stabilize the peptide in its soluble, unordered conformation, thereby preventing its misfolding and aggregation. This multi-methodological investigation revealed novel interactions between Aß1-42 and CORMs, contributing new insights into the proposed neuroprotective mechanisms mediated by CORMs and disclosing a new strategy to divert amyloid aggregation and toxicity.
ABSTRACT
In the cold environments of the interstellar medium, a variety of molecules in which a hydrogen (H) atom has been replaced by its heavier isotope deuterium (D) can be found. From its emergence, life had to counteract the toxic action of many agents, which posed a constant threat to its development and propagation. Oxygen-reactive species are archaic toxicants that lead to protein damage and genomic instability. Most of the oxidative lesions involve cleavage of C-H bonds and H abstraction. According to free radical chemistry principles, the substitution of D for H in oxidation-sensitive positions of cellular components should confer protection against the oxidative attack without compromising the chemical identity of the compounds. Here, we show that deuterated nucleosides and proteins protect from oxidative damage. Our data suggest a new, subtle but likely role of D in terrestrial life's evolution in that its inclusion in critical biomolecules might have facilitated their resistance during the infinite generations of life entities, cells, and organisms.
Subject(s)
Deuterium/chemistry , Oxidative Stress , Cell Survival/drug effects , Cell-Free System , DNA Damage/drug effects , Free Radicals/chemistry , Glycation End Products, Advanced/analysis , Humans , Jurkat Cells , Nucleosides/chemistry , Nucleosides/metabolism , Nucleosides/pharmacology , Oxidative Stress/drug effects , Protein Carbonylation , Proteins/chemistry , Proteins/metabolismABSTRACT
The two human monoamine oxidase isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason are well-known and attractive pharmacological targets in neuropsychiatric and neurodegenerative diseases, for which novel pharmacological approaches are necessary. Benextramine is a tetraamine disulfide mainly known as irreversible α-adrenergic antagonist, but able to hit additional targets involved in neurodegeneration. As the molecular structures of monoamine oxidases contain nine cysteine residues, the aim of this study was to evaluate benextramine and eleven structurally related polyamine disulfides as potential MAO inhibitors. Most of the compounds were found to induce irreversible inactivation of MAOs with inactivation potency depending on both the polyamine structure and the enzyme isoform. The more effective compounds generally showed preference for MAO B. Structure-activity relationships studies revealed the key role played by the disulfide core of these molecules in the inactivation mechanism. Docking experiments pointed to Cys323, in MAO A, and Cys172, in MAO B, as target of this type of inhibitors thus suggesting that their covalent binding inside the MAO active site sterically impedes the entrance of substrate towards the FAD cofactor. The effectiveness of benextramine in inactivating MAOs was demonstrated in SH-SY5Y neuroblastoma cell line. These results demonstrated for the first time that benextramine and its derivatives can inactivate human MAOs exploiting a mechanism different from that of the classical MAO inhibitors and could be a starting point for the development of pharmacological tools in neurodegenerative diseases.
Subject(s)
Cystamine/analogs & derivatives , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Cystamine/chemistry , Cystamine/pharmacology , Enzyme Activation/drug effects , Humans , Molecular Structure , Monoamine Oxidase/chemistry , Structure-Activity RelationshipABSTRACT
Small molecules able to bind non-canonical G-quadruplex DNA structures (G4) have been recently tested as novel potential agents for the treatment of prostate cancer thanks to their repression of aberrant androgen receptor gene. However, metastatic castration-resistant prostate cancer (mCRPC), a letal form of prostate cancer, is still incurable. Here we tested two naphthalenediimide derivatives, previously reported as multitarget agents, on a couple of relevant mCRPC cell models (DU145 and PC-3). We showed that these compounds interfere with the RAS/MEK/ERK and PI3K/AKT pathways. Interestingly, both these two biological processes depend upon Epidermal Growth Factor Receptor (EGFR) activation. By means of biological and analytical tools we showed that our compounds are efficient inducers of the structural transition of the EGFR promoter towards a G-quadruplex conformation, ultimately leading to a reduction of the receptor production. The overall result is an interesting cytotoxic profile for these two derivatives. Thanks to their activity at different steps, these compounds can open the way to novel therapeutic approaches for mCRPC that could contribute to escape resistance to selective treatments.
Subject(s)
DNA/metabolism , G-Quadruplexes/drug effects , Naphthalimides/pharmacology , Cell Line, Tumor , DNA/genetics , Drug Screening Assays, Antitumor , ErbB Receptors/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Ligands , MAP Kinase Signaling System/drug effects , Male , Naphthalimides/chemistry , Naphthalimides/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapyABSTRACT
Histone deacetylase inhibitors (HDACIs) are responsible for controlling gene expression by modulating the acetylation status of histone proteins. Furthermore, they modulate the activity of cytoplasmic non-histone proteins. Due to the involvement of HDACs in neurodevelopment, memory formation, and cognitive processes, HDACIs have been suggested as innovative agents for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Given their mechanisms of action and the complex nature of AD, HDACIs have been proposed for the design of novel multitarget ligands (MTLs). To this aim, the fragment responsible for HDAC inhibition has been coupled with other structures that are able to provide additional biological actions, such as antioxidant activity or the inhibition of phosphodiesteraseâ 5, transglutaminaseâ 2, and glycogen synthase kinaseâ 3ß. Herein we discuss recent efforts to design HDACI-based MTLs as potential disease-modifying entities.
Subject(s)
Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Drug Discovery , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Neuroprotective Agents/pharmacology , Alzheimer Disease/metabolism , Antioxidants/chemical synthesis , Antioxidants/chemistry , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Ligands , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistryABSTRACT
Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3ß (GSK-3ß), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H2O2 and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (<100 µM) and high water solubility.