Synthesis of guggulsterone derivatives as potential anti-austerity agents against PANC-1 human pancreatic cancer cells

  • Bioorg Med Chem Lett. 2020 Apr 1;30(7):126964. doi: 10.1016/j.bmcl.2020.126964.
Aki Kohyama  1 ,  Rei Yokoyama  1 ,  Dya Fita Dibwe  2 ,  Sahar El-Mekkawy  3 ,  Meselhy R Meselhy  4 ,  Suresh Awale  5 ,  Yuji Matsuya  6
Affiliations
  • 1. Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 2. Division of Natural Drug Discovery, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 3. Department of Chemistry of Natural Compounds, National Research Centre, Elbohouth St., Giza, Egypt.
  • 4. Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 5. Division of Natural Drug Discovery, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: [email protected].
  • 6. Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: [email protected].
PMID: 32057581 DOI: 10.1016/j.bmcl.2020.126964
Abstract

E- and Z-guggulsterones and nine guggulsterone derivatives (GSDs) were synthesized and evaluated for their preferential cytotoxicity against human PANC-1 cell in nutrient deprived medium utilizing antiausterity strategy. Among the synthesized compounds, GSD-1 and GSD-7 showed potent cytotoxicity against PANC-1 cells under nutrient-deprived conditions in a concentration dependent manner, with a PC50 value of 1.6 μM and 3.2 μM, respectively. The effect of GSD-1 and GSD-7 was further evaluated in a real time using live cell imaging. Both of these compounds altered PANC-1 cell morphology, leading to cell death at sub micromolar concentration range. GSD-1 and GSD-7 also inhibited PANC-1 cell colony formation in a concentration-dependent manner. GSD-1 and GSD-7 are lead structure for the anti-austerity drug development.

Keywords
Antiausterity agent; Drug discovery; Guggulsterone; PANC-1; Pancreatic cancer; Preferential cytotoxicity; Steroid.