Design, synthesis, and biological activities of 3-((4,6-diphenylpyrimidin-2-ylamino)methylene)-2,3-dihydrochromen-4-ones

  • Bioorg Chem. 2022 Mar;120:105634. doi: 10.1016/j.bioorg.2022.105634.
Soon Young Shin  1 ,  Euitaek Jung  1 ,  Hyunjin Yeo  1 ,  Seunghyun Ahn  2 ,  Youngshim Lee  3 ,  Jihyun Park  3 ,  Hyunook Kang  3 ,  Woon-Seok Yeo  3 ,  Dongsoo Koh  2 ,  Yoongho Lim  4
Affiliations
  • 1. Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
  • 2. Department of Applied Chemistry, Dongduk Women's University, Seoul 02748, Republic of Korea.
  • 3. Division of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
  • 4. Division of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea. Electronic address: [email protected].
PMID: 35114524 DOI: 10.1016/j.bioorg.2022.105634
Abstract

Novel (Z)-3-((4,6-diphenylpyrimidin-2-ylamino)methylene)-2,3-dihydrochromen-4-one derivatives were designed and synthesized to find chemotherapeutic agents. Derivative 9 was selected based on its clonogenicity against Cancer cells and synthetic yield for further biological experiments. It showed decreases in Aurora Kinase A, B, and C phosphorylation from western blot analysis. Derivative 9 upregulated the expression of G1 cell cycle inhibitory proteins including p21 and p27, and G1 progressive cyclin D1, and downregulated G1-to-S progressive cyclins, resulting in cell cycle arrest at the G1/S boundary. It stimulated the cleavage of caspase-9, -3, -7, and poly (ADP-ribose) polymerase, resulting in triggering Apoptosis through a caspase-dependent pathway. In addition, derivative 9 inhibited in vivo tumor growth in a syngeneic tumor implantation mouse model. The findings of this study suggest that derivative 9 can be considered as a lead compound for chemotherapeutic agents.

Keywords
3-(Pyrimidin-2-ylaminomethylene)-2; 3-Dihydrochromen-4-one; Anti-cancer; Apoptosis; Aurora kinases; Cell cycle arrest; Clonogenic long-term survival assay.
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