Research Article

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 and Correa-Basurto Jose*   Pages 1441 - 1454 ( 14 )

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. </P><P> 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. </P><P> Method: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations. </P><P> 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 &micro;M), acute myeloid leukemia (THP-1; IC50 = 16.5 &micro;M), human mast leukemia (HMC; IC50 = 79.29 &micro;M) and chronic myelogenous leukemia (Kasumi; IC50 = 101 &micro;M). </P><P> 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.

Affiliation:

Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Departamento de Quimica Organica, Escuela Nacional de Ciencias, Biologicas, Instituto Politecnico Nacional, Prolongacion de Carpio y Plan de Ayala, Col. Casco de Santo Thomas, Mexico City 11340, Laboratorio de Inmunologia Medica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Unidad Profesional Lazaro Cardenas, Avenida Salvador Diaz Miron s/n esquina Plan de San Luis, Col. Santo Tomas, Delegación Miguel Hidalgo 11340, Distrito Federal, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340, Centro de Nanociencias y Micro y Nanotecnologias (CNMN) del Instituto Politecnico Nacional, Av. Luis Enrique Erro S/N, Unidad Profesional Adolfo Lopez Mateos, Col. Zacatenco, Distrito Federal 07738, Laboratorio de Modelado Molecular, Diseno de farmacos y Bioinformatica, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, Plan de San Luis y Salvador Diaz Miron S/N, Col. Casco de Santo Tomas, Distrito Federal 11340

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