title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations.
  
  
  
  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).
  
  
  
  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.
authors.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. Mexico.
authors.forename: Rolando Alberto
authors.initials: RA
authors.lastname: Rodríguez-Fonseca
authors.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. Mexico.
authors.forename: Yudibeth
authors.initials: Y
authors.lastname: Sixto-López
authors.affiliation: 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. Mexico.
authors.forename: M Jonathan
authors.initials: MJ
authors.lastname: Fragoso-Vázquez
authors.affiliation: 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. Mexico.
authors.forename: Raul
authors.initials: R
authors.lastname: Flores-Mejía
authors.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. Mexico.
authors.forename: Laura Cristina
authors.initials: LC
authors.lastname: Cabrera-Pérez
authors.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. Mexico.
authors.forename: Ismael
authors.initials: I
authors.lastname: Vázquez-Moctezuma
authors.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. Mexico.
authors.forename: Martha Cecilia
authors.initials: MC
authors.lastname: Rosales-Hernández
authors.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. Mexico.
authors.forename: Martiniano
authors.initials: M
authors.lastname: Bello
authors.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. Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Archundia
authors.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. Mexico.
authors.forename: Jose Guadalupe
authors.lastname: Trujillo-Ferrara
authors.affiliation: 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. Mexico.
authors.forename: Elvia
authors.initials: E
authors.lastname: Becerra-Martínez
authors.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. Mexico.
authors.forename: Jose
authors.initials: J
authors.lastname: Correa-Basurto
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010654:Phenylbutyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C000623383:N-(4-chlorophenyl)-4-phenylbutanamide; D010654:Phenylbutyrates; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; Histone deacetylase 6; cancer; docking; drug design; leukemia cells