Structure-activity relationship and mechanistic study on guggulsterone derivatives; Discovery of new anti-pancreatic cancer candidate

  • Bioorg Med Chem. 2022 Jan 15;54:116563. doi: 10.1016/j.bmc.2021.116563.
Aki Kohyama  1 ,  Min Jo Kim  2 ,  Rei Yokoyama  1 ,  Sijia Sun  2 ,  Ashraf M Omar  2 ,  Nguyen Duy Phan  2 ,  Meselhy R Meselhy  3 ,  Kiyoshi Tsuge  4 ,  Suresh Awale  5 ,  Yuji Matsuya  6
Affiliations
  • 1. Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 2. Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 3. Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 4. Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.
  • 5. Natural Drug Discovery Laboratory, 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: 34942553 DOI: 10.1016/j.bmc.2021.116563
Abstract

Pancreatic Cancer is one of the deadliest types of malignancies. A new intervention aiming to combat pancreatic Cancer is targeting its extra-ordinary ability to tolerate nutrition starvation, a phenomenon known as "Austerity". As a part of a research program aiming to develop a new-generation of Anticancer agents, known as "anti-austerity agents", guggulsterone derivatives (GSDs) were identified as unique anti-austerity agents in terms of potency and selectivity. These agents are able to exert preferential cytotoxic activity only under nutrient-deprived conditions with little or no toxicity under normal conditions. In the present study, a library of 14 GSDs was synthesized and screened against PANC-1 human pancreatic cells. Among tested compounds, GSD-11 showed the most potent activity with PC50 a value of 0.72 μM. It also inhibited pancreatic Cancer cell migration and colony formation in a concentration-dependent manner. A mechanistic study revealed that this compound can inhibit the activation of the Akt/mTOR signaling pathway. Therefore, GSD-11 could be a promising lead compound for the Anticancer drug discovery against pancreatic Cancer.

Keywords
Anti-austerity agent; Drug discovery; Guggulsterone; Michael acceptor; Pancreatic cancer; Preferential cytotoxicity; Steroid.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146738
    GSD-11
    Antiausterity Agent
    target: Akt
    Research Areas: Cancer