Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities
Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydro...
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MDPI AG
2020-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/3/717 |
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| author | Na Zhao Feifei Yang Lina Han Yuhua Qu Di Ge Hua Zhang |
| author_facet | Na Zhao Feifei Yang Lina Han Yuhua Qu Di Ge Hua Zhang |
| author_sort | Na Zhao |
| collection | DOAJ |
| description | Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds <b>6</b> and <b>7</b> displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, <b>13a</b> and <b>13c</b>, showed potent anti-proliferative activities against solid tumor cell lines with IC<sub>50</sub> values of 0.36−2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that <b>13a</b> and <b>13c</b> dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, <b>13a</b> and <b>13c</b> arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound <b>13c</b>. |
| first_indexed | 2024-12-10T05:20:52Z |
| format | Article |
| id | doaj.art-f24e8019643e43488e88f12fecc24c59 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T05:20:52Z |
| publishDate | 2020-02-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f24e8019643e43488e88f12fecc24c592022-12-22T02:00:49ZengMDPI AGMolecules1420-30492020-02-0125371710.3390/molecules25030717molecules25030717Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor ActivitiesNa Zhao0Feifei Yang1Lina Han2Yuhua Qu3Di Ge4Hua Zhang5School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaHistone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds <b>6</b> and <b>7</b> displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, <b>13a</b> and <b>13c</b>, showed potent anti-proliferative activities against solid tumor cell lines with IC<sub>50</sub> values of 0.36−2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that <b>13a</b> and <b>13c</b> dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, <b>13a</b> and <b>13c</b> arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound <b>13c</b>.https://www.mdpi.com/1420-3049/25/3/717coumarinanti-tumorhdac inhibitorsstructural modificationanti-proliferative |
| spellingShingle | Na Zhao Feifei Yang Lina Han Yuhua Qu Di Ge Hua Zhang Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities Molecules coumarin anti-tumor hdac inhibitors structural modification anti-proliferative |
| title | Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities |
| title_full | Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities |
| title_fullStr | Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities |
| title_full_unstemmed | Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities |
| title_short | Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities |
| title_sort | development of coumarin based hydroxamates as histone deacetylase inhibitors with antitumor activities |
| topic | coumarin anti-tumor hdac inhibitors structural modification anti-proliferative |
| url | https://www.mdpi.com/1420-3049/25/3/717 |
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