Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

Anh, Duong Tien; Pham-The, Hai; Le-Thi-Thu, Huong; Park, Eun Jae; Jun, Hye Won; Kang, Jong Soon; Kwon, Joo-Hee; Dung, Do Thi Mai; Vu, Tran Anh; Hue, Van Thi My; Han, Sang‐Bae; Nam, Nguyen Hai

doi:10.1016/j.bioorg.2020.103988

Cited by 20 publications

(12 citation statements)

References 30 publications

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“…The redocked orientation was highly overlapped with the native ligand with the root-mean-square deviation of 0.8110Å and similar interactions such as H-bonds with residues His573, His574, Tyr745, and hydrophobic interactions with Pro464, Phe583, and Phe643. In the same manner, SAHA was docked into the active site of HDAC6 and showed key interactions with zinc ion and important catalytic residues His573, His574, and Tyr745 at the bottom of the pocket. ,, The lower binding energy of SAHA-HDAC6 in comparison to Belinostat could be attributed to the lack of multiple stacking contacts with backbone Phe583 and Pro464. The target binding energies of SAHA and Belinostat were calculated via the London and affinity scoring function implemented into MOE software (see Table ).…”

Section: Resultsmentioning

confidence: 96%

“…Based on the findings of Wu et al, hydroxamic acids should be deprotonated upon its binding to the zinc ion. The receptor was prepared using the QuickPrep module in MOE 2015.10, similar to those reported previously. , During the preparation, solvent and noncomplexed ions were deleted, Protonate3D was used for setting protonation states allowing ASN/GLN/HIS “Flips” in this function, polar hydrogen atoms were added, and all atoms were assigned AMBER FF99 force field. For the docking assays, the flexible ligand-rigid protein settings were applied using the MOE Triangle Matcher placement method, keeping the best 30 poses for conformational analysis.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…In the same manner, SAHA was docked into the active site of HDAC6 and showed key interactions with zinc ion and important catalytic residues His573, His574, and Tyr745 at the bottom of the pocket. 22,25,36 The lower binding energy of SAHA-HDAC6 in comparison to Belinostat could be attributed to the lack of multiple stacking contacts with backbone Phe583 and Pro464. The target binding energies of SAHA and Belinostat were calculated via the London and affinity scoring function implemented into MOE software (see Table 3).…”

Section: Docking Studiesmentioning

confidence: 99%

“…Recently, quinazoline-based hydroxamic acids designed as hybridized anticancer agents (e.g CUDC-101) have also been reported . We previously have also described several series of hydroxamic acids incorporating quinazoline or 4-oxoquinazoline systems with potent HDAC inhibitory and cytotoxic activities. ,− The addition of the 4-oxo functional group on the quinazoline rings was aimed at creating more hydrogen-bond interaction of the compounds with the amino acid chains located at the entrance of the enzyme active binding pocket. This paper describes the results obtained from the synthesis, biological evaluation, and docking study of these novel N -hydroxypropenamides.…”

Section: Introductionmentioning

confidence: 99%

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Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

et al. 2021

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Two series of novel 4-oxoquinazoline-based N-hydroxypropenamides (9a–m and 10a–m) were designed, synthesized, and evaluated for their inhibitory and cytotoxicity activities against histone deacetylase (HDAC). The compounds showed good to potent HDAC inhibitory activity and cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). In this series, compounds with the N-hydroxypropenamide functionality impeded at position 7 on the 4-oxoquinazoline skeleton (10a–m) were generally more potent than compounds with the N-hydroxypropenamide moiety at position 6 (9a–m). Also, the N 3-benzyl-substituted derivatives (9h–m, 10h–m) exhibited stronger bioactivity than the N 3-alkyl-substituted ones (9a–e, 10a–e). Two compounds 10l and 10m were the most potent ones. Their HDAC inhibitory activity (IC50 values, 0.041–0.044 μM) and cytotoxicity (IC50 values, 0.671–1.211 μM) were approximately 2- to 3-fold more potent than suberoylanilide hydroxamic acid (SAHA). Some compounds showed up to 10-fold more potent HDAC6 inhibition compared to their inhibitory activity in total HDAC extract assay. Analysis of selected compounds 10l and 10m revealed that these compounds strongly induced both early and late apoptosis and arrested SW620 cells at the G2/M phase. Docking studies were carried out on the HDAC6 isoform for series 10a–m and revealed some important features contributing to the inhibitory activity of synthesized compounds.

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Section: Resultsmentioning

confidence: 96%

Section: Experimental Sectionmentioning

confidence: 99%

Section: Docking Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

et al. 2021

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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][7][8][9][10][11][12][13][14][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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2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

Basri,

Fatima,

Jalil

et al. 2023

Archiv der Pharmazie

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Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long‐term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2‐oxoquinoline‐based thiosemicarbazones 9a–r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO‐A and MAO‐B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO‐A, MAO‐B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 μM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

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Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

Cited by 20 publications

References 30 publications

Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

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