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

Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma.

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Design, synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors

Bioorganic Chemistry ◽

10.1016/j.bioorg.2017.03.005 ◽

2017 ◽

Vol 72 ◽

pp. 32-41 ◽

Cited By ~ 19

Author(s):

Mamdouh F.A. Mohamed ◽

Montaser Sh.A. Shaykoon ◽

Mostafa H. Abdelrahman ◽

Bakheet E.M. Elsadek ◽

Ahmed S. Aboraia ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Docking Studies ◽

Biological Evaluation ◽

Design Synthesis ◽

Chalcone Derivatives

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Design, Synthesis and Biological Evaluation of Novel Coumarin-Based Hydroxamate Derivatives as Histone Deacetylase (Hdac) Inhibitors with Antitumor Activities

Molecules ◽

10.3390/molecules24142569 ◽

2019 ◽

Vol 24 (14) ◽

pp. 2569 ◽

Cited By ~ 8

Author(s):

Feifei Yang ◽

Na Zhao ◽

Jiali Song ◽

Kongkai Zhu ◽

Cheng-shi Jiang ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Hdac Inhibitors ◽

A549 Cells ◽

Docking Studies ◽

Biological Evaluation ◽

Hdac Inhibition ◽

Design Synthesis ◽

M Phase ◽

Ic50 Values

A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50 values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds 10e and 11d also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, 10e and 11d displayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover, 10e and 11d significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds 10e and 12a with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.

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Design, synthesis and preliminary biological evaluation of new hydroxamate histone deacetylase inhibitors as potential antileukemic agents

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2008.07.119 ◽

2008 ◽

Vol 18 (18) ◽

pp. 5071-5074 ◽

Cited By ~ 21

Author(s):

L. Guandalini ◽

C. Cellai ◽

A. Laurenzana ◽

S. Scapecchi ◽

F. Paoletti ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Biological Evaluation ◽

Design Synthesis

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

ACS Omega ◽

10.1021/acsomega.0c05870 ◽

2021 ◽

Vol 6 (7) ◽

pp. 4907-4920

Author(s):

Duong T. Anh ◽

Pham-The Hai ◽

Le D. Huy ◽

Hoang B. Ngoc ◽

Trinh T. M. Ngoc ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Biological Evaluation ◽

Design Synthesis ◽

Synthesis And Biological Evaluation

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STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i3.22735 ◽

2018 ◽

Vol 10 (3) ◽

pp. 90

Author(s):

Avineesh Singh ◽

Harish Rajak

Keyword(s):

Molecular Docking ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Research Work ◽

3D Qsar ◽

Qsar Model ◽

Docking Studies ◽

Inhibition Activity ◽

Design Strategies ◽

Histone Deacetylase 1

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.

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