Medicinal chemistry updates of novel HDACs inhibitors (2020 to present)

He, Xingrui; Hui, Zi; Xu, Li; Bai, Renren; Gao, Yuan; Wang, Zongcheng; Xie, Tian; Ye, Xiang‐Yang

doi:10.1016/j.ejmech.2021.113946

Cited by 46 publications

(27 citation statements)

References 95 publications

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“…They have been shown to be effective in a broad range of diseases, especially in cancer treatment, where they have been mainly applied to treat hematological malignancies. HDACi have also been shown to be potential treatments for metabolic diseases such as diabetes, neurodegenerative diseases such as Multiple sclerosis, viral infections such as HIV, and peripheral neuropathies such as Charcot–Marie–Tooth disease (CMT) [ 113 , 114 ].…”

Section: Hdacs Therapies: Approved Trials and Future Directionsmentioning

confidence: 99%

“…To date, at least 700 clinical trials are registered and more than 200 are currently recruiting participants. From 2011 to 2020 at least 2000 HDACi papers were published per year, with patents representing 6–11% of the total publications [ 113 ]. The global market for HDAC research has been predicted to grow by 32% annually [ 114 ].…”

Section: Hdacs Therapies: Approved Trials and Future Directionsmentioning

confidence: 99%

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Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Gomez-Sanchez

Patel

Martirena

et al. 2022

IJMS

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The peripheral nervous system (PNS) has a remarkable regenerative capacity in comparison to the central nervous system (CNS), a phenomenon that is impaired during ageing. The ability of PNS axons to regenerate after injury is due to Schwann cells (SC) being reprogrammed into a repair phenotype called Repair Schwann cells. These repair SCs are crucial for supporting axonal growth after injury, myelin degradation in a process known as myelinophagy, neurotropic factor secretion, and axonal growth guidance through the formation of Büngner bands. After regeneration, repair SCs can remyelinate newly regenerated axons and support nonmyelinated axons. Increasing evidence points to an epigenetic component in the regulation of repair SC gene expression changes, which is necessary for SC reprogramming and regeneration. One of these epigenetic regulations is histone acetylation by histone acetyl transferases (HATs) or histone deacetylation by histone deacetylases (HDACs). In this review, we have focused particularly on three HDAC classes (I, II, and IV) that are Zn2+-dependent deacetylases. These HDACs are important in repair SC biology and remyelination after PNS injury. Another key aspect explored in this review is HDAC genetic compensation in SCs and novel HDAC inhibitors that are being studied to improve nerve regeneration.

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Section: Hdacs Therapies: Approved Trials and Future Directionsmentioning

confidence: 99%

Section: Hdacs Therapies: Approved Trials and Future Directionsmentioning

confidence: 99%

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Gomez-Sanchez

Patel

Martirena

et al. 2022

IJMS

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“…According to current knowledge, HDAC inhibitors usually have several structural subunits: a zinc chelating group, a hydrophobic linker, and a hydrophobic (usually aromatic) cap [ 1 – 2 5 ]. One of the most commonly used zinc chelating groups in HDACs inhibitors is a hydroxamic acid moiety (–CONHOH) [ 6 – 15 ]. The ability of hydroxamic acids to form chelates with various metal cations, including the Zn 2+ ion found in the catalytic center of most HDAC proteins, gives them good biological activity in inhibiting these proteins.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

Jakubkienė

Valiulis

Schweipert

et al. 2022

Beilstein J. Org. Chem.

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Histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through the deacetylation of nuclear histone and non-histone proteins and are promising therapeutic targets for the treatment of various diseases. Here, the synthesis of new compounds in which a hydroxamic acid residue is attached 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 followed by aminolysis of the obtained esters with hydroxylamine. Oxidation of the 2-methylthio group to the methylsulfonyl group and following treatment with amines resulted in the formation of the corresponding 2-amino-substituted derivatives, the ester group of which reacted with hydroxylamine to give the corresponding hydroxamic acids. The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively.

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“…To form strong hydrophobic interactions with residues in the opening of active site, the 5-chloro-4-((substituted phenyl)amino)pyrimidine group is integrated into the cap moiety of HDAC inhibitors ( Figure 2 ). The pyrimidine motif is commonly utilised in the design of HDAC inhibitors, and the pyrimidine group plays an important role in improving the solubility of target molecules, enhancing the polar interactions between inhibitors and HDACs, and optimising pharmacokinetic parameters of HDAC inhibitors 15 , 16 . Currently, lack of efficacy against solid tumours in clinical trials restricted the application of HDAC inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Discovery and SAR analysis of 5-chloro-4-((substituted phenyl)amino)pyrimidine bearing histone deacetylase inhibitors

Zhang

Chen

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC 50 values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC 50 value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells.

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Medicinal chemistry updates of novel HDACs inhibitors (2020 to present)

Cited by 46 publications

References 95 publications

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

Discovery and SAR analysis of 5-chloro-4-((substituted phenyl)amino)pyrimidine bearing histone deacetylase inhibitors

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