2. Academic Validation
  3. Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation

Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation

  • Eur J Med Chem. 2021 Jun 5:218:113258. doi: 10.1016/j.ejmech.2021.113258.
Abdulrahim A Alzain 1,  Lucie Brisson 2,  Pierre-Olivier Delaye 3,  Mélanie Pénichon 3,  Stéphanie Chadet 4,  Pierre Besson 4,  Stéphan Chevalier 2,  Hassan Allouchi 3,  Magdi A Mohamed 5,  Sébastien Roger 6,  Cécile Enguehard-Gueiffier 7
Affiliations

Affiliations

  • 1 University of Tours, Faculty of Pharmacy, EA 7502 SIMBA, 31 Avenue Monge, 37200, Tours, France; University of Gezira, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, P.O box 20, Gezira, Sudan.
  • 2 University of Tours, INSERM, UMR 1069 N2C, 10 boulevard Tonnellé, 37032, Tours Cedex, France.
  • 3 University of Tours, Faculty of Pharmacy, EA 7502 SIMBA, 31 Avenue Monge, 37200, Tours, France.
  • 4 University of Tours, EA 4245 T2I, 10 boulevard Tonnellé, 37032, Tours Cedex, France.
  • 5 University of Khartoum, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Khartoum, Sudan; Jouf University, College of Pharmacy, Department of Pharmaceutical Chemistry, Saudi Arabia.
  • 6 University of Tours, EA 4245 T2I, 10 boulevard Tonnellé, 37032, Tours Cedex, France; Institut Universitaire de France, 75006, Paris, France. Electronic address: sebastien.roger@univ-tours.fr.
  • 7 University of Tours, Faculty of Pharmacy, EA 7502 SIMBA, 31 Avenue Monge, 37200, Tours, France. Electronic address: cecile.gueiffier@univ-tours.fr.
PMID: 33813152 DOI: 10.1016/j.ejmech.2021.113258
Abstract

Herein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent Anticancer activities in vitro with IC50 of 0.4-5 μM against three human Cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced Apoptosis in MDA-MB-231 cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the expression of pro-apoptotic Bax protein while 18-20 reduced the level of anti-apoptotic Bcl-2 protein. Compounds 18 and 19 also reduced MDA-MB-231 cells proliferation as measured by Ki-67 staining. Furthermore, compounds were also tested for the ability to inhibit cell migration in the highly aggressive human MDA-MB-435s cell line. Six compounds of this series (8, 15, 18, 22, 23, 24) inhibited cell migration by 41-50% while four compounds (20, 25, 27, 30) inhibited the migration by 53-62% in wound-healing experiments. Interestingly, compound 20 presented both antiproliferative and anti-migration activities and might be a promising anti-metastatic agent for Cancer treatment.

Keywords

Anti-migration activity; Antiproliferative activity; Harmine analogues; Imidazo[1,2-a:4,5-c’]dipyridines.

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