Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer
<b>Background</b>: Histone deacetylases (HDACs) are enzymes that deacetylate histone proteins, impacting the transcriptional repression and activation of cancer-associated genes such as P53 and Ras. The overexpression of HDACs in breast cancer (BC) underscores their significance as thera...
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2025-02-01
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| author | Gerardo Morales-Herrejón Juan Benjamín García-Vázquez Cynthia Fernández-Pomares Norbert Bakalara José Correa-Basurto Humberto L. Mendoza-Figueroa |
| author_facet | Gerardo Morales-Herrejón Juan Benjamín García-Vázquez Cynthia Fernández-Pomares Norbert Bakalara José Correa-Basurto Humberto L. Mendoza-Figueroa |
| author_sort | Gerardo Morales-Herrejón |
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| description | <b>Background</b>: Histone deacetylases (HDACs) are enzymes that deacetylate histone proteins, impacting the transcriptional repression and activation of cancer-associated genes such as P53 and Ras. The overexpression of HDACs in breast cancer (BC) underscores their significance as therapeutic targets for modulating gene expression through epigenetic regulation. <b>Methods</b>: In this study, a novel series of SAHA (suberoylanilide hydroxamic acid) analogs were designed using an in silico ligand-based strategy. These analogs were then synthesized and evaluated for their HDAC-inhibitory capacity as well as their antiproliferative capacity on breast cancer cells. These compounds retained an aliphatic LINKER, mimicking the natural substrate acetyl-lysine, while differing from the hydroxamic fragment present in SAHA. <b>Results</b>: The synthesized compounds exhibited HDAC inhibitory activity, suggesting potential for binding to these pharmacological targets. Compounds <b>5b</b>, <b>6a</b>, and <b>6b</b> were identified as promising candidates in the evaluation on breast cancer cell lines MCF-7 and MDA-MB-231 at 72 h. Specifically, compound <b>6b</b>, which contains an <i>N</i>-trifluoroacetyl group as a zinc-binding group (ZBG), demonstrated an IC<sub>50</sub> of 76.7 µM in the MDA-MB-231 cell line and 45.7 µM in the MCF-7 cell line. In the non-tumorigenic cell line, the compound exhibited an IC<sub>50</sub> of 154.6 µM. Conversely, SAHA exhibited an almost negligible safety margin with regard to its cytotoxic activity when compared to breast cancer cells and healthy cells (MCF-10A). This observation underscores the elevated toxicity exhibited by hydroxamic acid-derived molecules. <b>Conclusions</b>: The bioisosteric modification of ZBG by <i>N</i>-trifluoroacetyl in <b>6a</b> and <b>6b</b> demonstrated favorable cytotoxic activity, exhibiting a higher safety margin. This study underscores the challenge of identifying novel ZBGs to replace hydroxamic acid in the development of HDAC inhibitors, with the objective of enhancing their physicochemical and toxicological profile for utilization in BC treatment. |
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| spelling | doaj-art-1bf33cdbaf4444b48367cd79b0af5e562025-08-20T02:42:24ZengMDPI AGPharmaceuticals1424-82472025-02-0118335110.3390/ph18030351Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast CancerGerardo Morales-Herrejón0Juan Benjamín García-Vázquez1Cynthia Fernández-Pomares2Norbert Bakalara3José Correa-Basurto4Humberto L. Mendoza-Figueroa5Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina del Instituto Politécnico Nacional (ESM-IPN), Plan de San Luis y Salvador Díaz Mirón S/N, Casco de Santo Tomás, Ciudad de México 11340, MexicoLaboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina del Instituto Politécnico Nacional (ESM-IPN), Plan de San Luis y Salvador Díaz Mirón S/N, Casco de Santo Tomás, Ciudad de México 11340, MexicoLaboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina del Instituto Politécnico Nacional (ESM-IPN), Plan de San Luis y Salvador Díaz Mirón S/N, Casco de Santo Tomás, Ciudad de México 11340, MexicoUniversity Bordeaux, CNRS, Bordeaux INP-ENSTBB, CBMN, UMR 5248, F-33600 Pessac, FranceLaboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina del Instituto Politécnico Nacional (ESM-IPN), Plan de San Luis y Salvador Díaz Mirón S/N, Casco de Santo Tomás, Ciudad de México 11340, MexicoLaboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina del Instituto Politécnico Nacional (ESM-IPN), Plan de San Luis y Salvador Díaz Mirón S/N, Casco de Santo Tomás, Ciudad de México 11340, Mexico<b>Background</b>: Histone deacetylases (HDACs) are enzymes that deacetylate histone proteins, impacting the transcriptional repression and activation of cancer-associated genes such as P53 and Ras. The overexpression of HDACs in breast cancer (BC) underscores their significance as therapeutic targets for modulating gene expression through epigenetic regulation. <b>Methods</b>: In this study, a novel series of SAHA (suberoylanilide hydroxamic acid) analogs were designed using an in silico ligand-based strategy. These analogs were then synthesized and evaluated for their HDAC-inhibitory capacity as well as their antiproliferative capacity on breast cancer cells. These compounds retained an aliphatic LINKER, mimicking the natural substrate acetyl-lysine, while differing from the hydroxamic fragment present in SAHA. <b>Results</b>: The synthesized compounds exhibited HDAC inhibitory activity, suggesting potential for binding to these pharmacological targets. Compounds <b>5b</b>, <b>6a</b>, and <b>6b</b> were identified as promising candidates in the evaluation on breast cancer cell lines MCF-7 and MDA-MB-231 at 72 h. Specifically, compound <b>6b</b>, which contains an <i>N</i>-trifluoroacetyl group as a zinc-binding group (ZBG), demonstrated an IC<sub>50</sub> of 76.7 µM in the MDA-MB-231 cell line and 45.7 µM in the MCF-7 cell line. In the non-tumorigenic cell line, the compound exhibited an IC<sub>50</sub> of 154.6 µM. Conversely, SAHA exhibited an almost negligible safety margin with regard to its cytotoxic activity when compared to breast cancer cells and healthy cells (MCF-10A). This observation underscores the elevated toxicity exhibited by hydroxamic acid-derived molecules. <b>Conclusions</b>: The bioisosteric modification of ZBG by <i>N</i>-trifluoroacetyl in <b>6a</b> and <b>6b</b> demonstrated favorable cytotoxic activity, exhibiting a higher safety margin. This study underscores the challenge of identifying novel ZBGs to replace hydroxamic acid in the development of HDAC inhibitors, with the objective of enhancing their physicochemical and toxicological profile for utilization in BC treatment.https://www.mdpi.com/1424-8247/18/3/351histone deacetylasesHDAC inhibitorshydroxamic acidzinc binding groupmolecular dockingADMET |
| spellingShingle | Gerardo Morales-Herrejón Juan Benjamín García-Vázquez Cynthia Fernández-Pomares Norbert Bakalara José Correa-Basurto Humberto L. Mendoza-Figueroa Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer Pharmaceuticals histone deacetylases HDAC inhibitors hydroxamic acid zinc binding group molecular docking ADMET |
| title | Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer |
| title_full | Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer |
| title_fullStr | Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer |
| title_full_unstemmed | Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer |
| title_short | Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based on <i>N</i>-Trifluoroacetamide as a Zinc-Binding Group, Against Breast Cancer |
| title_sort | computationally guided design synthesis and evaluation of novel non hydroxamic histone deacetylase inhibitors based on i n i trifluoroacetamide as a zinc binding group against breast cancer |
| topic | histone deacetylases HDAC inhibitors hydroxamic acid zinc binding group molecular docking ADMET |
| url | https://www.mdpi.com/1424-8247/18/3/351 |
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