10521-06-9Relevant articles and documents
Histone Deacetylase 2 (HDAC2) Inhibitors Containing Boron
Kavianpour, Poya,Gemmell, Madeleine C. M.,Kahlert, Jan U.,Rendina, Louis M.
, p. 2786 - 2791 (2020)
Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50=40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50=42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.
Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA)
Calder, Ewen D. D.,Conway, Stuart J.,Folkes, Lisa K.,Hammond, Ester M.,Mistry, Ishna N.,Skwarska, Anna,Sneddon, Deborah
, (2020)
Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21percent oxygen) or physoxia (4–7.5percent oxygen) and hypoxia (2.0percent oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in 0.1percent oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.
Perfluorinated HDAC inhibitors as selective anticancer agents
Walton, James W.,Cross, Jasmine M.,Riedel, Tina,Dyson, Paul J.
, p. 9186 - 9190 (2017)
A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new
Process Development of the Soft Histone Deacetylate Enzyme Inhibitor SHP-141: Acylation of Methyl Paraben and Suberyl Hydroxamic Acid Formation
Deng, Yijun,Ng Dimarco, Christina,Vakhilt, Tanya,Jonas, Marco,White, Jaclyn,Arefyev, Dennis,Tokala, Ramachandar,Akhtar, Parveen,Zhu, Lei,Sun, Xufeng,Haimowitz, Thomas,Condon, Stephen M.
, p. 1812 - 1820 (2016)
SHP-141 (1) is a hydroxamic acid-based inhibitor of histone deacetylase enzymes which is under development for the treatment of cutaneous T-cell lymphoma. The original synthesis of 1 involved five synthetic steps beginning with suberic acid monomethyl ester. Final deprotection of the O-benzyl hydroxamate moiety using hydrogen and palladium catalyst mandated the use of metal scavengers to reduce palladium levels to within International Council for Harmonisation (ICH) guidance. Owing to the sensitivity of 1 toward self-condensation and the potential for N-O bond cleavage under hydrogenolytic conditions, we developed an alternative route to 1 which avoids Pd-mediated hydrogenation and prolonged metal scavenger treatment. This two-step process employs readily available suberic acid and methyl paraben and has successfully delivered multiple kilograms of 1 for clinical use. Importantly, crude 1 was stabilized for recrystallization in acetonitrile (ACN) solution by the addition of 0.1% citric acid and 4% water. Additionally, the filtration and drying of suitably sized aggregates of 1 with high purity (100 area%) was accomplished via temperature cycling of the 1/ACN solution.
Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors
Zhang, Song,Huang, Weibin,Li, Xiaonan,Yang, Zhicheng,Feng, Binghong
, p. 795 - 804 (2015)
The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid (SAHA) had been designed as potential histone deacetylase inhibitors (HDACis). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC8 than SAHA. Compounds 1-5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines (MGR2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect (HDAC, IC50 = 0.1187 μm; U251, IC50 = 0.8949 μm) and lower toxicity for human normal cells (LO2, IC50 = 172.5 μm and MRC5, IC50 = 213.6 μm) compared with SAHA (HDAC, IC50 = 0.8717 μm; U251, IC50 = 8.938 μm; LO2, IC50 = 86.52 μm and MRC5, IC50 = 81.02 μm). In addition, N3F obviously increased Beclin-1 and Caspase-3 and 9 as well as inhibited Bcl-2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.
Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer
Tang, Chu,Li, Changhao,Zhang, Silong,Hu, Zhiye,Wu, Jun,Dong, Chune,Huang, Jian,Zhou, Hai-Bing
, p. 4550 - 4572 (2015)
A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In th
Molecular umbrella as a nanocarrier for antifungals
Skwarecki, Andrzej S.,Martynow, Dorota,Milewska, Maria J.,Milewski, S?awomir
, (2021/09/20)
A molecular umbrella composed of two O‐sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a “trimethyl lock” (TML) or o‐dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates
Design, synthesis, and biological evaluation of HDAC degraders with CRBN E3 ligase ligands
Li, Jia,Lu, Wei,Lu, Yingxin,Shao, Yingying,Su, Mingbo,Sun, Danwen,Xiao, Donghuai,Zhou, Yubo,Zhu, Shulei
, (2021/12/02)
Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).
Unified Total Synthesis of Five Bufadienolides
Hagiwara, Koichi,Inoue, Masayuki,Itoh, Hiroaki,Shimizu, Shinsuke
supporting information, (2020/11/13)
We report a unified total synthesis of five bufadienolides: bufalin (1), bufogenin B (2), bufotalin (3), vulgarobufotoxin (4), and 3-(N-succinyl argininyl) bufotalin (5). After the steroidal ABCD ring 8 was produced, the D ring was cross-coupled with a 2-pyrone moiety and stereoselectively epoxidized to generate 6. TMSOTf promoted a stereospecific 1,2-hydride shift from 6 to establish the β-oriented 2-pyrone of 19. Functional group manipulations from 19 furnished 1-5, which potently inhibited cancer cell growth.
Compound and pharmaceutical application thereof
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Paragraph 0019; 0021, (2018/12/13)
The invention discloses a compound and a pharmaceutical application thereof. The compound can be used as a corresponding inhibitor or a drug for treating disease through UHRF1 and HDAC double-targeting small chemical molecules or pharmaceutically acceptable salts of the small chemical molecules, so that the compound can be used for treating myelodysplastic syndrome, psoriasis, scar hyperplasia, prostate or mammary gland hyperplasia, blood tumors and solid cancers alone or in combination with other methods. The treatment effect is quite good.
