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

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.

• Authors: Rolando Alberto Rodríguez-Fonseca, Yudibeth Sixto-López, M Jonathan Fragoso-Vázquez, Raul Flores-Mejía, Laura Cristina Cabrera-Pérez, Ismael Vázquez-Moctezuma, Martha Cecilia Rosales-Hernández, Martiniano Bello, M Martínez-Archundia, Jose Guadalupe Trujillo-Ferrara, Elvia Becerra-Martínez, Jose Correa-Basurto
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 17 Issue 10 Pg. 1441-1454 ( 2017) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 28044941 (Publication Type: Journal Article)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Anilides
• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• N-(4-chlorophenyl)-4-phenylbutanamide
• Phenylbutyrates
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Anilides (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Histone Deacetylase 6
• Histone Deacetylase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Histone Deacetylases (metabolism)
• Humans
• Leukemia (drug therapy, pathology)
• Molecular Dynamics Simulation
• Molecular Structure
• Phenylbutyrates (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Uterine Cervical Neoplasms (drug therapy, pathology)