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

Aki Kohyama; Rei Yokoyama; Dya Fita Dibwe; Sahar El-Mekkawy; Meselhy R Meselhy; Suresh Awale; Yuji Matsuya

doi:10.1016/j.bmcl.2020.126964

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. Epub 2020 Jan 11.

Authors

Aki Kohyama¹, Rei Yokoyama¹, Dya Fita Dibwe², Sahar El-Mekkawy³, Meselhy R Meselhy⁴, Suresh Awale⁵, Yuji Matsuya⁶

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: suresh@inm.u-toyama.ac.jp.
⁶ Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: matsuya@pha.u-toyama.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Pancreatic Neoplasms / drug therapy*
Pregnenediones / chemical synthesis
Pregnenediones / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Pregnenediones
pregna-4,17-diene-3,16-dione