Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.

Reversible acetylation at the epsilon-amino group of lysines located at the conserved domain of core histones is supposed to play an important role in the regulation of chromatin structure and its transcriptional activity. One promising strategy for analyzing the precise function of histone acetylation is to block the activities of acetylating or deacetylating enzymes by specific inhibitors. Recently, two microbial metabolites, trichostatin A and trapoxin, were found to be potent inhibitors of histone deacetylases. Trichostatin A reversibly inhibits the mammalian histone deacetylase, whereas trapoxin causes inhibition through irreversible binding to the enzyme. The histone deacetylase from a trichostatin A-resistant cell line is resistant to trichostatin A, indicating that the enzyme is the primary target. Both of the agents induce a variety of biological responses of cells such as induction of differentiation and cell cycle arrest. Trichostatin A and trapoxin are useful in analyzing the role of histone acetylation in chromatin structure and function as well as in determining the genes whose activities are regulated by histone acetylation.

Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function.

This invention relates to iminodiacetic acid and diamine hydroxamic acid derivatives, that are inhibitors of histone deacetylase (HDAC), and are useful in the prevention and/or treatment of cellular proliferative diseases, for example cancer, autoimmune, allergic and inflammatory diseases, diseases of the central nervous system (CNS) such as neurodegenerative diseases, and in the prevention and/or treatment of restenosis.

/pdf/histone-deacetylase-inhibitors-2kscxj8vod.pdf

Histone deacetylase inhibitors

https://www.cell.com/structure/pdf/S0969-2126(04)00159-5.pdf

Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases

FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor.

Biological activities of four chemically synthesized trichostatin-related compounds, (R)-trichostatin A, (S)-trichostatin A, (R)-trichostatic acid, and (S)-trichostatic acid, were investigated. Assays of differentiation-inducing activity in Friend leukemia cells and G2-arresting activity in the cell cycle of normal rat fibroblast cells were used as monitoring systems for comparing the bioactivities of these compounds. The results clearly showed that both of the enantiomers of trichostatic acid had no activity in both the assay systems. In the case of (S)-trichostatin A, the antipode of naturally occurring trichostatin A, 50% effective concentrations were determined to be 50-70-fold higher than those of (R)-trichostatin A. The relationship between this ratio and the value of enantiomeric excess strongly suggests that (S)-trichostatin A is also biologically inactive. These results indicate that the absolute configuration and the presence of the hydroxamate group of trichostatin A are essential for its biological activity.

Structural specificity for biological activity of trichostatin A, a specific inhibitor of mammalian cell cycle with potent differentiation-inducing activity in Friend leukemia cells.

Synthesis of trichostatin a, a potent differentiation inducer of friend leukemic cells, and its antipode

Total Synthesis of (‐)‐Periplanone‐B, the Sex Pheromone of the American Cockroach.

The enantioselective synthesis of (–)-allosamizoline (2a), the aminocyclitol moiety of allosamidin (1a), was achieved by starting from D-glucosamine (3). Intramolecular nitrile oxide cycloaddition was adopted as the key step to construct a functional cyclopentane ring system with proper stereochemistry.

Synthesis of (–)-Allosamizoline, the Pseudoaminosugar Moiety of Allosamidin, a Chitinase Inhibitor

Both enantiomers of phoracantholide I and J were synthesized from a chiral starting material obtainable via yeast reduction, and the absolute configurations of the natural materials were determined by GLC studies using a chiral stationary phase.

Koshi Koseki

Papers

Structural specificity for biological activity of trichostatin A, a specific inhibitor of mammalian cell cycle with potent differentiation-inducing activity in Friend leukemia cells.

Synthesis of trichostatin a, a potent differentiation inducer of friend leukemic cells, and its antipode

Total Synthesis of (‐)‐Periplanone‐B, the Sex Pheromone of the American Cockroach.

Synthesis of (–)-Allosamizoline, the Pseudoaminosugar Moiety of Allosamidin, a Chitinase Inhibitor

The Synthesis and the Absolute Configuration of Phoracantholide I and J; The Defensive Secretion of the Eucarypt Longicorn, Phoracantha synonyma