Design, Synthesis and Biological Evaluation of a Phenyl Butyric Acid Derivative, N-(4-chlorophenyl)-4-phenylbutanamide: A HDAC6 Inhibitor with Anti-proliferative Activity on Cervix Cancer and Leukemia Cells

Author(s): Rodriguez-Fonseca Rolando Alberto , Sixto-Lopez Yudibeth , Fragoso-Vazquez M. Jonathan , Flores-Mejia Raul , Cabrera-Perez Laura Cristina , Vazquez-Moctezuma Ismael , Rosales-Hernandez Martha Cecilia , Bello Martiniano , Martinez-Archundia M , Trujillo-Ferrara Jose Guadalupe , Becerra-Martinez Elvia , Correa-Basurto Jose* .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , Issue 10 , 2017

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Abstract:

Background: The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc.

Objective: Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference.

Method: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations.

Results: These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM).

Conclusion: These results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.

Keywords: Histone deacetylase 6, cancer, drug design, docking, HDAC6, leukemia cells.

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Article Details

VOLUME: 17
ISSUE: 10
Year: 2017
Page: [1441 - 1454]
Pages: 14
DOI: 10.2174/1871520617666170103092851
Price: $58

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