2. Academic Validation
  3. Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects

Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects

  • Bioorg Chem. 2020 Aug;101:104019. doi: 10.1016/j.bioorg.2020.104019.
Abdallah Turky 1,  Ashraf H Bayoumi 1,  Adel Ghiaty 1,  Adel S El-Azab 2,  Alaa A-M Abdel-Aziz 3,  Hamada S Abulkhair 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt.
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 3 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
  • 4 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University - Egypt, International Costal Road, New Damietta, Egypt. Electronic address: [email protected].
PMID: 32615465 DOI: 10.1016/j.bioorg.2020.104019
Abstract

The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10-32 was evaluated in human hepatocellular carcinoma (HePG-2), breast Cancer (MCF-7), prostate Cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83-13.97 μM), similar to doxorubicin (IC50, 4.17-8.87 μM) and afatinib (IC50, 5.4-11.4 μM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06-10.5 μM), similar to doxorubicin (IC50, 4.50 μM) and afatinib (IC50, 5.4 μM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83-10.36 and 5.69-11.36 μM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 μM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56-12.28 μM) compared with doxorubicin (IC50, 8.87 µM) and afatinib (IC50 7.7 μM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 μM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 μM, respectively) compared with bromosporine (IC50, 5.00 μM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 μM), inducing Apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.

Keywords

1,2,4-triazolophthalazine scaffold; Antitumor activity; Apoptosis induction; PCAF-inhibition; Synthesis.

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