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

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

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.

Keywords


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

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DOI: http://dx.doi.org/10.29356/jmcs.v61i4.460

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Copyright (c) 2018 Luis Bahena, Carlos Cervantes, Karla J Soto-Arredondo, Minerva Martínez-Alfaro, Natanael Zarco, Marco A. García-Revilla, Yolanda Alcaraz-Contreras, Lourdes Palma Tirado, Miguel A. Vázquez, Juvencio Robles

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Journal of the Mexican Chemical Society (J. Mex. Chem. Soc.) Vol 61, No 4 (2017). Quarterly publication (October-December). Edited and distributed by Sociedad Química de México, A.C. Barranca del Muerto 26, Col. Crédito Constructor, Del. Benito Juárez, C.P. 03940, Mexico City. Phone: +5255 56626837; +5255 56626823 Contact: soquimex@sqm.org.mx http://www.sqm.org.mx Editor-in-Chief: Ignacio González-Martínez. Indexed Journal. Certificate of reserved rights granted by the Instituto Nacional del Derecho de Autor (INDAUTOR): 04-2005-052710530600-102. Certificate of lawful title and content: Under procedure. ISSN-e granted by the Instituto Nacional del Derecho de Autor (INDAUTOR): 2594-0317. ISSN granted by the Instituto Nacional del Derecho de Autor (INDAUTOR): 1870-249X. Postal registration of printed matter deposited by editors or agents granted by SEPOMEX: IM09-0312 Copyright © Sociedad Química de México, A.C. Total or partial reproduction is prohibited without written permission of the right holder. The Figures/schemes quality and the general contents of this publication are full responsibility of the authors. Updated April 24th, 2018 by Adriana Vázquez (editorial assistant, e-mail: editor.jmcs@gmail.com), J. Mex. Chem. Soc., Sociedad Química de México, A.C.