New Pyrazole/Pyrimidine-Based Scaffolds as Inhibitors of Heat Shock Protein 90 Endowed with Apoptotic Anti-Breast Cancer Activity

• Main Authors: Lamya H. Al-Wahaibi (Author), Mohammed A. I. Elbastawesy (Author), Nader E. Abodya (Author), Bahaa G. M. Youssif (Author), Stefan Bräse (Author), Sara N. Shabaan (Author), Galal H. Sayed (Author), Kurls E. Anwer (Author)
• Format: Book
• Published: MDPI AG, 2024-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph17101284; 1424-8247
• Keywords: pyrimidine; pyrazole; microwave; breast cancer; Hsp90; apoptosis; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 17, Iss 10, p 1284 (2024)

<b>Background/Objectives</b>: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. <b>Methods</b>: The newly synthesized compounds were analyzed with IR, ¹³C NMR, ¹H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. <b>Results</b>: Pyrimidine-containing scaffold compounds <b>9</b> and <b>10</b> were the most active, achieving IC₅₀ = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds <b>9</b> and <b>10</b> showed a remarkable inhibitory activity against the Hsp90 protein with IC₅₀ values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC₅₀ = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound <b>9</b> were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. <b>Conclusions</b>: Compounds <b>9</b> and <b>10</b> may have apoptotic antiproliferative action as Hsp90 inhibitors.