Novel Aminopyrimidine-2,4-diones, 2-Thiopyrimidine-4-ones, and 6-Arylpteridines as Dual-Target Inhibitors of BRD4/PLK1: Design, Synthesis, Cytotoxicity, and Computational Studies

• Main Authors: Samar El-Kalyoubi (Author), Samiha A. El-Sebaey (Author), Sherin M. Elfeky (Author), Hanan A. AL-Ghulikah (Author), Mona S. El-Zoghbi (Author)
• Format: Book
• Published: MDPI AG, 2023-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Structural-based drug design and solvent-free synthesis were combined to obtain three novel series of 5-arylethylidene-aminopyrimidine-2,4-diones (<b>4</b>, <b>5a</b>-<b>c</b>, <b>6a</b>,<b>b</b>), 5-arylethylidene-amino-2-thiopyrimidine-4-ones (<b>7</b>,<b>8</b>), and 6-arylpteridines (<b>9</b>,<b>10</b>) as dual BRD4 and PLK1 inhibitors. MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. The most active compounds were tested against normal Vero cells. Compounds <b>4</b> and <b>7</b> significantly inhibited BRD4 and PLK1, with IC₅₀ values of 0.029, 0.042 µM, and 0.094, 0.02 µM, respectively, which are nearly comparable to volasertib (IC₅₀ = 0.017 and 0.025 µM). Compound <b>7</b> triggered apoptosis and halted cell growth at the G2/M phase, similarly to volasertib. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates.

Item Description

10.3390/ph16091303
1424-8247