Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Abstract

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 6 and 7 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, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c 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, 13a and 13c 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 13c.

Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against Pseudomonas aeruginosa

“…In this study, we used a hybridization strategy to design and synthesize a lot of coumarin-hydroxamic acid derivatives − and successfully conducted a hit-to-lead campaign, resulting in a dual-acting biofilm inhibitor as an antibacterial synergist. The hit compound 4t has the lowest IC 50 value at 3.66 μM and exhibited promising antibiofilm activity for P. aeruginosa.…”

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies

“…Even that, only a few recent studies include a computational characterization of coumarin based compounds as a HDAC Inhibitor. Regarding with this, Zhang and coworkers in recent research indicate the effectiveness of having a coumarin moiety as the main structure for its modification and application as anticancer agents, in combination with an hydroxamic acid functionalization to potentialize the activity ( Figure 2) [24][25][26]. This kind of information is a strong background to embrace the hypothesis of the present work.…”

“…Greater sensitivity to antiproliferative activity was shown by the breast versus prostate cancer cells. Zhao et al obtained similar results where coumarin-containing hydroxamate HDAC inhibitors were more potent to inhibit MDA-MB-231 cell proliferation compared with lung adenocarcinoma cell lines [26]. The compounds exhibiting the strongest antiproliferative activity were 7c, 7e, 7f and 7i, substituted with H, 6-MeO, 8-EtO and 6-Br, respectively.…”

Coumarin based-histone deactylace HADC inhibitors

“…10a and Furthermore 10b arrest ed MDA-MB-231 cells at G2/M phase and induced cell apoptosis. Moreover, Immunoblot analysis exhibited that 1a and 10b increased the acetylation of histone H3 and H4 in dose-dependent manner confirming their HDAC1 inhibitory activities [29] . Among them, compound 11f was known as the most potent HDAC inhibitor in this series with( IC50 = 0.32 μM), which was more effective than that of SAHA (IC50 = 0.48 μM).…”