Dona Flor and her two husbands: Discovery of novel HDAC6/AKT2 inhibitors for myeloid cancer treatment.

Unlabelled: Hematological cancer treatment with hybrid kinase/HDAC inhibitors is a novel strategy to overcome the challenge of acquired resistance to drugs. We collected IC datasets from the ChEMBL database for 13 cancer cell lines (72 h cytotoxicity, measured by MTT), known inhibitors for 38 kinases, and 10 HDACs isoforms, that we identified by target fishing and literature review. The data was subjected to rigorous biological and chemical curation leaving the final datasets ranging from 76 to 8173 compounds depending on the target.

Effect of different design and surface treatment on the load-to-failure of ceramic repaired with composite.

Unlabelled: Glass ceramics are widely used to manufacture esthetic veneers, inlays, onlays, and crowns. Although the clinical survival rates ofglass-ceramic restorations arefavorable,fractures or chips are common. Certain cases can be repaired with direct composite.

1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors.

We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a-d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers.

HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents.

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC ≤ 50 nM) vs.

Posture monitoring in healthcare: a systematic mapping study and taxonomy.

Palliative treatments for back pain usually include exercise, analgesics, physiotherapy, prostheses, and surgery in severe cases. Technologies for postural monitoring are growing, and they are important in preventing back pain and mitigating permanent damage. Remote work, especially after the COVID-19 pandemic, made people spend more time than usual in chairs and environments not certified by the health aspects of work.

Galvanic vestibular stimulation and its applications: a systematic review.

Objective: Galvanic vestibular stimulation has been evaluated in the context of vestibular rehabilitation. The objective was to identify evidence in the scientific literature about the clinical applications of galvanic vestibular stimulation.

Methods: In this systematic review, the articles describing the applications of galvanic vestibular stimulation were extracted from PubMed, Web of Science, MEDLINE, Scopus, LILACS and SciELO databases.

Rational Design, Synthesis, and Mechanism of (3,4)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase.

Human ornithine aminotransferase (hOAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators ( and ).

Design of Novel Phosphopantetheine Adenylyltransferase Inhibitors: A Potential New Approach to Tackle Mycobacterium tuberculosis.

Background: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths.

Turnover and Inactivation Mechanisms for ()-3-Amino-4,4-difluorocyclopent-1-enecarboxylic Acid, a Selective Mechanism-Based Inactivator of Human Ornithine Aminotransferase.

The inhibition of human ornithine δ-aminotransferase (OAT) is a potential therapeutic approach to treat hepatocellular carcinoma. In this work, ()-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, ) was identified as a potent mechanism-based inactivator of OAT while showing excellent selectivity over other related aminotransferases (e.g.

Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model.

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 ().

Peppers: A "Hot" Natural Source for Antitumor Compounds.

, , and are the main genera of peppers consumed worldwide. The traditional use of peppers by either ancient civilizations or modern societies has raised interest in their biological applications, including cytotoxic and antiproliferative effects. Cellular responses upon treatment with isolated pepper-derived compounds involve mechanisms of cell death, especially through proapoptotic stimuli in tumorigenic cells.

A computational model for adaptive recording of vital signs through context histories.

Wearable devices emerged from the advancement of communication technology and the miniaturization of electronic components. These devices periodically monitor the user's vital signs and generally have a short battery life. This work introduces ODIN, a model for optimized vital signs collection based on adaptive rules.

Structure-activity relationship and mechanistic studies for a series of cinnamyl hydroxamate histone deacetylase inhibitors.

Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential anticancer HDACis.

Antiophidic activity of the secondary metabolite lupeol isolated from Zanthoxylum monogynum.

Previous studies have demonstrated the potential antiophidic activity of Zanthoxylum monogynum A.St.-Hil.

Mercaptoacetamide: A promising zinc-binding group for the discovery of selective histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) is a zinc-dependent HDAC that mainly modulates the acetylation status of non-histone substrates, such as α-tubulin and heat shock protein 90 (HSP90). The activity of HDAC6 plays a critical role in cell proliferation, protein trafficking and degradation, cell shape, migration, as well as regulation of immunomodulatory factors. For this reason, HDAC6 influences the progress of cancers, neurodegenerative disorders, and autoimmune responses.

Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models.

Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms.

Enterococci from Wild Magellanic Penguins (Spheniscus magellanicus) as an Indicator of Marine Ecosystem Health and Human Impact.

Enterococci are commensals that proliferated as animals crawled ashore hundreds of millions of years ago. They are also leading causes of multidrug-resistant hospital-acquired infections. While most studies are driven by clinical interest, comparatively little is known about enterococci in the wild or the effect of human activity on them.

Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors.

The enzyme dihydrofolate reductase from M.tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds.

Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models.

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors.

Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling.

The use of molecules inspired by natural scaffolds has proven to be a very promising and efficient method of drug discovery. In this work, capsaicin, a natural product from Capsicum peppers with antitumor properties, was used as a prototype to obtain urea and thiourea analogues. Among the most promising compounds, the thiourea compound 6g exhibited significant cytotoxic activity against human melanoma A2058 cells that was twice as high as that of capsaicin.

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT).

Crystal Structure of GenD2, an NAD-Dependent Oxidoreductase Involved in the Biosynthesis of Gentamicin.

Gentamicins are clinically relevant aminoglycoside antibiotics produced by several Micromonospora species. Gentamicins are highly methylated and functionalized molecules, and their biosynthesis include glycosyltransferases, dehydratase/oxidoreductases, aminotransferases, and methyltransferases. The biosynthesis of gentamicin A from gentamicin A2 involves three enzymatic steps that modify the hydroxyl group at position 3″ of the unusual garosamine sugar to provide its substitution for an amino group, followed by an N-methylation.