In silico, Synthesis and Biological Investigations of Pyrrolo[3,4-C]Pyrrole Hydroxamic Acid Derivatives as Potential Anticancer Agents

Authors

  • Luis Bahena Universidad de Guanajuato
  • Carlos Cervantes Universidad de Guanajuato
  • Karla J Soto-Arredondo Universidad de Guanajuato
  • Minerva Martínez-Alfaro Universidad de Guanajuato
  • Natanael Zarco Universidad de Guanajuato
  • Marco A. García-Revilla Universidad de Guanajuato
  • Yolanda Alcaraz-Contreras Universidad de Guanajuato
  • Lourdes Palma Tirado UNAM
  • Miguel A. Vázquez Universidad de Guanajuato
  • Juvencio Robles Universidad de Guanajuato

DOI:

https://doi.org/10.29356/jmcs.v61i4.460

Keywords:

Molecular docking studies, DFT, pyrrolo[3, 4-c]pyrrole hydroxamic acid, synthesis, antiproliferative activity, HDAC, biological assays.

Abstract

Based in a general structural pharmacophore model of suberoylanilide hydroxamic acid (commercially known as Vorinostat©), we synthesized a series of new pyrrolo[3,4-c]pyrrole hydroxamic acid derivatives, 9a-c, to be tested as candidates for anti-cancer drugs. The evaluation of their possible biological activity was assessed in two ways: a) computational characterization from molecular calculations and quantum reactivity descriptors and b) biological assays. Molecular docking and density functional theory calculations were performed to assess the binding properties of our newly synthesized pyrrolo[3,4-c] pyrrole hydroxamic acid derivatives, employing as the biological target the histone deacetylase isoforms available in the protein data bank. Furthermore, to characterize the effect of changing the functional groups that we varied while designing our drug model, and to improve the assessment of the binding energy, conceptual density functional theory reactivity descriptors were calculated to rationalize the capability of the new drugs to interact with the histones active site. Our findings show that the newly synthesized derivative, 9c, display the best energetic coupling with the biological target and the more favorable values of the density functional theory descriptors to interact with the active site. The biological assay of the anti-cancer drug candidates was done using three different techniques: i) anti-proliferative activity on two breast cancer cell lines; ii) Histone H3 acetylation; and iii) DNA damage. Docking studies were performed on histone deacetylase enzymes. The biological function of these enzymes is the deacetylation of histones. We analyze the level of histone acetylation in two cell lines. The computational findings are in good agreement with the biological evaluation. Our main contribution is that one of our newly synthesized derivatives, 9c, performs better than the commercial reference suberoylanilide hydroxamic acid.

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Author Biographies

Luis Bahena, Universidad de Guanajuato

Departamento de Farmacia, División de Ciencias Naturales y Exactas

Carlos Cervantes, Universidad de Guanajuato

Departamento de Química, División de Ciencias Naturales y Exactas

Karla J Soto-Arredondo, Universidad de Guanajuato

Departamento de Farmacia, División de Ciencias Naturales y Exactas

Minerva Martínez-Alfaro, Universidad de Guanajuato

Departamento de Farmacia, División de Ciencias Naturales y Exactas

Natanael Zarco, Universidad de Guanajuato

Departamento de Farmacia, División de Ciencias Naturales y Exactas

Marco A. García-Revilla, Universidad de Guanajuato

Departamento de Química, División de Ciencias Naturales y Exactas

Yolanda Alcaraz-Contreras, Universidad de Guanajuato

Departamento de Farmacia, División de Ciencias Naturales y Exactas

Lourdes Palma Tirado, UNAM

Instituto de Neurobiología

Miguel A. Vázquez, Universidad de Guanajuato

Departamento de Química, División de Ciencias Naturales y Exactas

Juvencio Robles, Universidad de Guanajuato

Departamento de Farmacia, División de Ciencias Naturales y Exactas

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Published

2018-01-30

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