Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors

• Main Authors: Omnia R. Elbatrawy (Author), Mohamed Hagras (Author), Moshira A. El Deeb (Author), Fatimah Agili (Author), Maghawry Hegazy (Author), Ahmed A. El-Husseiny (Author), Mahmoud Mohamed Mokhtar (Author), Samy Y. Elkhawaga (Author), Ibrahim H. Eissa (Author), Samar El-Kalyoubi (Author)
• Format: Book
• Published: MDPI AG, 2023-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<b>Background</b>: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. <b>Aim</b>: Discovery of new anticancer agents targeting HDAC. <b>Methods</b>: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. <b>Results</b>: Compounds <b>5a</b>, <b>5b</b>, <b>5f</b>, <b>5i</b>, <b>5k</b>, and <b>5m</b> exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound <b>5m</b> was the most potent member (IC₅₀ = 0.05 µg/mL) compared to trichostatin A (IC₅₀ = 0.0349 µg/mL). For HDAC4, compound <b>5m</b> showed superior activity (IC₅₀ = 2.83 µg/mL) than trichostatin A (IC₅₀ = 3.349 µg/mL)<b>.</b> Compound <b>5m</b> showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound <b>5m</b> showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. <b>Conclusions</b>: Compound <b>5m</b> has potential anticancer activity targeting HDAC with a significant apoptotic effect.

Item Description

10.3390/ph16070966
1424-8247