Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities

  • Bioorg Med Chem Lett. 2017 Oct 15;27(20):4682-4686. doi: 10.1016/j.bmcl.2017.09.013.
Jia-Li Song  1 ,  Juan Zhang  2 ,  Chang-Liang Liu  3 ,  Chao Liu  4 ,  Kong-Kai Zhu  1 ,  Fei-Fei Yang  1 ,  Xi-Gong Liu  1 ,  João Paulo Figueiró Longo  2 ,  Luis Alexandre Muehlmann  2 ,  Ricardo Bentes Azevedo  5 ,  Yu-Ying Zhang  6 ,  Yue-Wei Guo  7 ,  Cheng-Shi Jiang  8 ,  Hua Zhang  9
Affiliations
  • 1. School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 2. Faculty of Ceilandia, University of Brasilia, Brasilia 72220275, Brazil; Institute of Biological Sciences, University of Brasília, Brasília 70910900, Brazil.
  • 3. Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 4. Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan 250100, China.
  • 5. Institute of Biological Sciences, University of Brasília, Brasília 70910900, Brazil.
  • 6. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
  • 7. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 8. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
  • 9. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
PMID: 28919340 DOI: 10.1016/j.bmcl.2017.09.013
Abstract

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel Anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50=2.5μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50=6.5-36.2μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in Cancer chemotherapy.

Keywords
2-Cyanoacryloyl; Anti-proliferative activity; Michael acceptor; NF-κB; Pregnenolone.