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  3. Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells

Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells

  • Bioorg Chem. 2022 May;122:105752. doi: 10.1016/j.bioorg.2022.105752.
Mohamed A Abdelgawad 1,  Fatma E A Mohamed 2,  Phoebe F Lamie 2,  Syed N A Bukhari 3,  Mohammad M Al-Sanea 3,  Arafa Musa 4,  Mohammed Elmowafy 5,  A A Nayl 6,  Ahmed Karam Farag 7,  Sameeha M Ali 8,  Mohamed E Shaker 9,  Hany A Omar 10,  Mohammed K Abdelhameid 11,  Manal M Kandeel 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia. Electronic address: mhmdgwd@ju.edu.sa.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 3 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 4 Department of Pharmacognosy, College of Pharmacy, Jouf University, 72341 Sakaka, Saudi Arabia.
  • 5 Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
  • 6 Department of Chemistry, College of Science, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 7 Manufacturing Department, Curachem Inc., Chungcheongbuk-do 28161, Republic of Korea.
  • 8 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
  • 9 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia.
  • 10 College of Pharmacy, University of Sharjah, United Arab Emirates.
  • 11 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: mohamedabdelwahab976@yahoo.com.
PMID: 35339926 DOI: 10.1016/j.bioorg.2022.105752
Abstract

Dual inhibition of Topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using Topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against Topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against Topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both Enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC Apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of Apoptosis, and late-stage Apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several Apoptosis biomarkers such as p53, TNFα, Caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against Topo II and FLT3 Enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both Enzymes.

Keywords

Acridine; And pseudo-pyrido-acridones; FLT3 kinase; Leukemia; Pyrido-dipyrimidines; Topoisomerase II.

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