Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate

• both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively. Keywords: alkylation; aminolysis; HDAC inhibitors; hydroxamic acid; pyrimidine; Introduction Histone deacetylases (HDACs) are a family of intracellular proteins responsible for removing acetyl groups in histones

• their catalytic site, while the remaining 7 isoforms of class III, known as sirtuins, are dependent on the NAD+ coenzyme [3][4]. According to current knowledge, HDAC inhibitors usually have several structural subunits: a zinc chelating group, a hydrophobic linker, and a hydrophobic (usually aromatic

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• direct access to cyclopeptides related to naturally occurring histone deacetylase (HDAC) inhibitors Cyl-1 and Cyl-2. Late stage modifications on the unsaturated amino acid side chain allow the introduction of functionalities which might coordinate to metal ions in the active center of metalloproteins

• ]. Three of these enzyme classes (I, II, and IV) contain Zn2+ within the active site, and therefore these enzymes can be affected by typical Zn2+-binding HDAC inhibitors. In cellular systems, an acetylated lysine of a histone is entering the cavity of the active site and gets coordinated to Zn2

• +. Subsequent attack of water forms a tetrahedral intermediate which results in a cleavage of the acetylated lysine. Most HDAC inhibitors act as substrate mimics and contain a zinc-binding motif. They competitively interact with the HDACs to form stable intermediates and therewith block the active site. Many

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• , an immunoactivating natural product (substrate 37) [97][98]. In 2015, the diastereoselective synthesis of (E,S)-3-hydroxy-7-tritylthio-4-heptenoic acid 43, a key component of cyclodepsipeptide histone deacetylase (HDAC) inhibitors, was achieved in flow (Scheme 4) [99]. Acetyloxazolidinone 41 was used

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• development of novel HDAC inhibitors (HDACis) has become a rapidly evolving area where targeted inhibition has emerged in clinical research as a potential therapeutic approach for the treatment of various cancers as well as neurodegenerative disorders and immune related diseases [3][4][5]. Of specific

• interests are Class I HDAC isozymes, HDAC2 and HDAC8, which are important targets in cancer models as both are associated with high risk diseases such as prostate cancer and neuroblastoma [6][7][8]. Compounds such as vorinostat, givinostat and panobinostat have been successfully applied as HDAC inhibitors

• prepared for docking using Sylbyl-X 2.1. A protocol defining the regions of hydrogen donor, acceptor and hydrophobic character was created using the SFXC protocol [41][42][43]. The Zn2+ ion which is known to be essential in the hydroxamate class of HDAC inhibitors was included in the preparation of the

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• advantage. In continuation of our earlier studies [26][27] on HDAC inhibitors, we herein report a direct access to α,ß-unsaturated hydroxamates through cross-metathesis reaction. Results and Discussion It is known that a CM reaction between a class-I olefin and a class-II olefin proceeds better in the

• of the important cyclic peptide Chap-31 may encourage the preparation of cyclic peptide based HDAC inhibitors. The developed methodology may hence complement the existing literature on the preparation of such class of compounds and may find applications. Experimental General procedure for cross

Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides

• Shital Kumar Chattopadhyay,
• Suman Sil and
• Jyoti Prasad Mukherjee

Beilstein J. Org. Chem. 2017, 13, 2153–2156, doi:10.3762/bjoc.13.214

• of peptidomimetics. A cross-metathesis reaction has been utilized to create the diversification on the template 11 in order to obtain orthogonally protected Asu derivatives. Moreover, the Asu derivative 15a has been demonstrated to be useful in the preparation of a plethora of HDAC inhibitors [34

• , 32.2, 31.4, 28.3, 28.1, 23.8 ppm; HRMS (TOF–MS ES+) m/z: [M + Na]+ calcd for C18H31NNaO6, 380.2049; found, 380.2056. Biologically active naturally occurring cyclic tetrapeptide HDAC inhibitors. Reagents and conditions: (i) Triethyl phosphonoacetate, n-Bu4N+I−, aq K2CO3, rt, 18 h, 86%; (ii) H2, Pd/C

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• , treatment with 32 prolonged the post-onset survival of SOD1 H46R animals [68]. These studies indicate that the attenuation of oxidative-stress pathways through the upregulation of antioxidant genes can reduce disease progression in ALS models. Novel mechanisms Histone deacetylase (HDAC) inhibitors: Several

• of gene sequences to transcriptional complexes. SOD1 G93A mice have markedly reduced histone acetylation following disease onset as compared to control animals [71][72], supporting a role for aberrant transcriptional activity in disease progression. Consequently, histone deacetylase (HDAC) inhibitors

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• potent and isoform selective HDAC inhibitor. Here we report our preliminary studies on thioester HDAC inhibitors derived from the active monomeric (thiol) form of psammaplin A, as a means to improve compound delivery into cells. We have discovered that such compounds exhibit both potent cytotoxicity and

• name Zolinza by Merck & Co.) and romidepsin 2 (trade name Istodax by Celgene) for the treatment of cutaneous T-cell lymphoma (CTCL, Figure 1) [12][13][14]. The success of these compounds in the clinic has led to a significant interest in the further discovery of structurally novel HDAC inhibitors that

• , in particular, exhibit improved isoform selectivity. Among the myriad of previously reported HDAC inhibitors, psammaplin A [15][16][17][18] (3, X = OH, Scheme 1, left) displays an intriguing structure. It is a symmetric, dimeric hydroxyiminotyrosine-based natural product, characterised in 1987, and