Franz-Josef Meyer-Almes

Zinc-dependent histone deacetylases (HDACs) are found in all species, ranging from bacteria to eukaryotes. They catalyze the removal of acetyl groups or various organic acid residues, including fatty acids, from proteins or polyamines. These enzymes are located in various cellular compartments, and their function is modulated by their ability to form different protein complexes. HDACs are prominent targets in the study of human diseases and infections, but they have also recently been considered as targets for fungicides. The active sites of HDACs are highly conserved, both structurally and sequentially. Therefore, the development of isoenzyme-selective inhibitors poses an exceptionally great challenge. In this study, a chemical profiling approach was used to classify human HDAC isoenzymes, bacterial homologs, and mutant variants by function and to identify specific ligand-binding patterns. While the recognition profiles generally reflected established HDAC classes, HDAC8 exhibited significant differences from HDAC1–3. In contrast, HDAC6 demonstrated substantial similarity with HDAC1–3 despite their low sequence identity, distinguishing itself from the sequentially closely related HDAC10. These findings demonstrate that sequence similarity alone is not a reliable predictor of ligand recognition and underscore the importance of local active-site architecture and physicochemical properties. Zebrafish HDAC10 closely resembles human HDAC10, supporting its use as a functional surrogate, while bacterial homologs display distinct profiles that suggest opportunities for species-selective inhibitor development. A single active-site substitution in class IIa HDAC4 (H976Y) shifted its recognition profile from HDAC class IIa toward class I. Engineered HDAC11 variants showed substantially improved recombinant expression and comparable stability while retaining wild-type-like ligand recognition. This supports their use in screening, biophysical, and structural studies. Together, these results establish ligand recognition profiling as a practical approach for functionally classifying HDACs and guiding the development of selective inhibitors.

Histone deacetylase 8 (HDAC8) has emerged as a promising therapeutic target due to its role in epigenetic regulation.

Boron‐containing compounds have become an important class of scaffolds in medicinal chemistry, broadening the chemical space available for drug discovery. This review summarizes progress and key advances reported over the past 5 years in the development of bioactive boron‐based heterocycles and related systems, including BN‐indoles, azaborines, benzoxazaborines, benzodiazaborines, benzoxaborinines, benzoxaboroles, and boronic acid derivatives. These motifs act as bioisosteres of carbon frameworks and impart distinct physicochemical properties such as increased polarity, improved solubility, and enhanced hydrogen‐bonding capabilities. Several examples highlight their therapeutic relevance. Azaborine‐based histone deacetylase (HDAC) inhibitors and BN‐indole derivatives show potent nanomolar enzyme inhibition. Benzoxaboroles have reached clinical relevance, including antifungal drugs such as tavaborole and crisaborole, as well as late‐stage candidates like epetraborole and acoziborole. Benzoxaborinines and olaparib isosteres exhibit activity against carbonic anhydrases and PARP enzymes, while boronic acid drugs such as bortezomib and ixazomib are established proteasome inhibitors used in cancer therapy. Additional applications include antiviral, antibacterial, antiparasitic, and anti‐inflammatory activities, for example Leishmania CPSF3 inhibitors and P2X7 receptor antagonists. Despite these advances, challenges remain regarding potency, pharmacokinetics, and mechanistic understanding of boron–target interactions. Overall, boron‐based bioisosteres represent a versatile platform for developing new therapeutics across diverse disease areas.

Histone deacetylase 8 (HDAC8) is a clinically validated target in neuroblastoma, where isoform selective inhibition offers a strategy to suppress tumour growth while limiting off‐target toxicity. Hydroxamic acids remain the dominant zinc‐binding group (ZBG) in HDAC inhibitors but are also associated with metabolic instability, suboptimal pharmacokinetics and nonspecific metal chelation. In this study, we report the biological evaluation of a focussed library of 51 squaric acid derivatives as alternative, non‐hydroxamic HDAC inhibitors. While a subset of these compounds has been described previously in a synthetic context, their HDAC inhibitory activity and selectivity have not been reported to date. The compounds organised into four structural subfamilies were screened against HDAC8 with moderate isoform selectivity. Structure activity relationships, supported by molecular docking and in silico techniques, highlight the influence of substitution pattern, electronic properties and molecular rigidity on HDAC8 inhibition. Collectively, these findings establish squaric acid derivatives as a viable non‐hydroxamic acid scaffold for the development of selective HDAC inhibitors.

Histone deacetylase 8 (HDAC8) is a key enzyme involved in regulating gene expression and tumor development, positioning it as an attractive target for neuroblastoma. In this work, we designed and synthesized a novel series of substituted [1,2,4]Triazolo[4,3-a]quinoline derivatives to investigate their potential as HDAC8 inhibitors. Structural insights into their inhibitory activity were gained through molecular docking studies, highlighting critical interactions within the HDAC8 active site. To assess the stability of these interactions, molecular dynamics simulations were performed, confirming that the compounds maintained strong and stable binding within the HDAC8 enzyme. The most promising inhibitors 9h and 9m demonstrated significant efficacy in IMR-32 neuroblastoma cells, but had much weaker effects on the HCT116 and MCF7 cancer cell lines, as well as on the normal control cell line, HEK293. Further biological evaluations, including colony formation and cell migration assays, revealed their potential to inhibit the growth and spread of neuroblastoma tumor cells. Additional studies on cell cycle progression, apoptosis induction, and SMC3 acetylation indicated increased acetylation levels without altering total SMC3 protein levels, suggesting effective HDAC8 target engagement. In summary, comprehensive molecular modelling and biological assessments have demonstrated the strong potential of these non-hydroxamate-based HDAC8 inhibitors for treating neuroblastoma.

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design.

Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce the water solubility of the molecules, which is a disadvantage during application. To address this problem, azaborine rings may be substituted for conventional aromatic ring systems. These are obtained by replacing two adjacent carbon atoms with boron and nitrogen. Incorporating B–N analogs in place of aromatic rings not only enhances structural diversity but also provides a strategy to navigate around patent-protected scaffolds. We synthesized azaborines, which are isosteric to naphthalene and indole, and utilized them as capping units for HDAC inhibitors. These molecules were attached to various aliphatic and aromatic linkers with different zinc-binding units, used in established active compounds. Nearly half of the twenty-four molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three compounds displaying IC50 values in the nanomolar range. We have therefore demonstrated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop active substances containing azaborine rings against other targets.

Statistical design of experiments (DoE) is a key method for the systematic planning, execution, and analysis of experiments. In academia, it enables efficient scientific study design, particularly in the natural and engineering sciences, by identifying complex relationships between variables while reducing experimental effort. In industry, especially in the chemical, pharmaceutical, and manufacturing sectors, DoE is used to optimize processes, identify critical parameters, ensure quality, and meet regulatory standards. It supports resource conservation, shortens development times, enhances product quality, and reduces costs. This laboratory practical is offered to Master’s students in the Chemical Technology and Biotechnology program. It aims to lower the cost of a glucose assay while ensuring a robust response signal that enables the safe detection of 0.125 mM d -glucose by employing an enzyme activity model. Students first design an efficient experimental plan using DoE software, followed by hands-on implementation of the experiments and statistical evaluation of the results. Through this process, they learn to apply DoE for optimizing complex, multivariable systems, and will develop a comprehensive understanding of the effect that various factors and their interactions have on the response signal. The skills and insights gained are broadly transferable to a range of experimental and industrial challenges, particularly in the natural sciences.

Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce water solubility of the molecules, which is a disadvantage during application. To address this problem, azaborine rings may be substituted for conventional aromatic ring systems. These are obtained by replacing two adjacent carbon atoms with boron and nitrogen. Incorporating B–N analogues in place of aromatic rings not only enhances structural diversity but also provides a strategy to navigate around patent-protected scaffolds. We synthesized azaborines, which are isosteric to naphthalene and indole and utilized them as capping units for HDAC inhibitors. These molecules were attached to various aliphatic and aromatic linkers with different zinc-binding units, used in established active compounds. Nearly half of the 24 molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three com-pounds displaying IC₅₀ values in the nanomolar range. We have therefore demon-strated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop ac-tive substances containing azaborine rings against other targets.