https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

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

The Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. Depending upon the stimulus and cell type, this pathway can transmit signals, which result in the prevention or induction of apoptosis or cell cycle progression. Thus, it is an appropriate pathway to target for therapeutic intervention. This pathway becomes more complex daily, as there are multiple members of the kinase and transcription factor families, which can be activated or inactivated by protein phosphorylation. The diversity of signals transduced by this pathway is increased, as different family members heterodimerize to transmit different signals. Furthermore, additional signal transduction pathways interact with the Raf/MEK/ERK pathway to regulate positively or negatively its activity, or to alter the phosphorylation status of downstream targets. Abnormal activation of this pathway occurs in leukemia because of mutations at Ras as well as genes in other pathways (eg PI3K, PTEN, Akt), which serve to regulate its activity. Dysregulation of this pathway can result in autocrine transformation of hematopoietic cells since cytokine genes such as interleukin-3 and granulocyte/macrophage colony-stimulating factor contain the transacting binding sites for the transcription factors regulated by this pathway. Inhibitors of Ras, Raf, MEK and some downstream targets have been developed and many are currently in clinical trials. This review will summarize our current understanding of the Ras/Raf/MEK/ERK signal transduction pathway and the downstream transcription factors. The prospects of targeting this pathway for therapeutic intervention in leukemia and other cancers will be evaluated.

Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention

The epigenome is defined by DNA methylation patterns and the associated posttranslational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The silencing of gene expression is associated with deacetylated histones, which are often found to be associated with regions of DNA methylation as well as methylation at the lysine 4 residue of histone 3. In contrast, the activation of gene expression is associated with acetylated histones and methylation at the lysine 9 residue of histone 3. The histone deactylases play a major role in keeping the balance between the acetylated and deacetylated states of chromatin. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are similar to the yeast RPD3 protein and localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are homologous to the yeast HDA1 protein and are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are similar to the yeast SIR2 proteins. Since inappropriate silencing of critical genes can result in one or both hits of tumor suppressor gene (TSG) inactivation in cancer, theoretically the reactivation of affected TSGs could have an enormous therapeutic value in preventing and treating cancer. Indeed, several HDAC inhibitors are currently being developed and tested for their potency in cancer chemotherapy. Importantly, these agents are also potentially applicable to chemoprevention if their toxicity can be minimized. Despite the toxic side effects and lack of specificity of some of the inhibitors, progress is being made. With the elucidation of the structures, functions and modes of action of HDACs, finding agents that may be targeted to specific HDACs and potentially reactivate expression of only a defined set of affected genes in cancer will be more attainable.

Histone deacetylases: unique players in shaping the epigenetic histone code.

New cyclotetrapeptides, trapoxins A and B were isolated from the culture broth of Helicoma ambiens RF-1023. These compounds exhibit detransformation activities against v-sis oncogene-transformed NIH3T3 cells (sis/NIH3T3) as antitumor agents. The structures were found to be new cyclotetrapeptides, cyclo[(S)-phenylalanyl-(S)-phenylalanyl-(R)-pipecolinyl- (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoyl-] for trapoxin A and cyclo[(S)-phenylalanyl-(S)-phenylalanyl-(R)-prolyl-2- amino-8-oxo-9,10-epoxydecanoyl-] for trapoxin B, by X-ray analysis, mass spectrometric, NMR and chemical studies.

Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents.

A novel compound depudecin inducing the flat phenotype of ras- and src- transformed NIH3T3 cells at a concentration of 1 μg/ml was isolated from the culture broth of Alternaria brassicicola. Based on its spectroscopic characteristics and X-ray crystallographic analysis of its bis-(1S)-(-)-camphanate, the structure of depudecin was determined'to be (2R, 3S, 4S, 5E, lS, 8S, 9R)-2, 9-dihydroxy3, 4;7, 8-diepoxy-undeca-5, 10-diene.

Depudecin: a novel compound inducing the flat phenotype of NIH3T3 cells doubly transformed by ras- and src-oncogene, produced by Alternaria brassicicola.

New inhibitors of aldose reductase, designated salfredins A3, A4, A7, C1, C2, C3 and B11, were isolated from the fermentation broth of Crucibulum sp. RF-3817 by successive purification procedures of solvent extraction, silica gel column chromatographies and reverse-phase HPLC. Their structures were established by spectroseopic methods, including UV, SI-MS and NMR. The structures of salfredins A4 and B11 were confirmed by X-ray crystallographic analysis.

https://www.jstage.jst.go.jp/article/antibiotics1968/48/6/48_6_439/_pdf

Salfredins, new aldose reductase inhibitors produced by Crucibulum sp. RF-3817. I. Fermentation, isolation and structures of salfredins.

Thielocins A2 alpha, A2 beta, A3, B1, B2 and B3 were isolated as a novel family of phospholipase A2 inhibitors from the fermentation broth of Thielavia terricola RF-143 together with thielavins and thielocins A1 alpha and A1 beta. The most potent inhibitory activity (IC50 = 0.0033 microM) against rat group II phospholipase A2 was shown by thielocin A1 beta. Against human group II phospholipase A2, thielocin B3 (IC50 = 0.076 microM) was the most potent.

Isolation and biological activity of thielocins: novel phospholipase A2 inhibitors produced by Thielavia terricola RF-143.

New antibiotics, agglomerins A, B, C and D, were isolated from the culture broth of a bacterial strain identified as Enterobacter agglomerans. These antibiotics are acidic in nature and their sodium salts are obtained as colorless crystalline powders, soluble in lower alcohols. All the antibiotics shows characteristic UV maxima at 248 and 298 nm. Molecular formulas: A, C15H21O4Na; B, C17H23O4Na; C, C17H25O4Na and D, C19H27O4Na; were indicated by elemental analysis and MS. These antibiotics are active against a wide variety of anaerobic bacteria and weakly against aerobic Gram-positive bacteria in vitro.

Nobuo Uotani

Papers

Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents.

Depudecin: a novel compound inducing the flat phenotype of NIH3T3 cells doubly transformed by ras- and src-oncogene, produced by Alternaria brassicicola.

Salfredins, new aldose reductase inhibitors produced by Crucibulum sp. RF-3817. I. Fermentation, isolation and structures of salfredins.

Isolation and biological activity of thielocins: novel phospholipase A2 inhibitors produced by Thielavia terricola RF-143.

Isolation and characterization of agglomerins A, B, C and D.