Design and synthesis of functionalized coumarins as potential anti-austerity agents that eliminates cancer cells' tolerance to nutrition starvation

Suresh Awale; Takahiro Okada; Dya Fita Dibwe; Takahiro Maruyama; Satoyuki Takahara; Takuya Okada; Satoshi Endo; Naoki Toyooka

doi:10.1016/j.bmcl.2019.05.010

Design and synthesis of functionalized coumarins as potential anti-austerity agents that eliminates cancer cells' tolerance to nutrition starvation

Bioorg Med Chem Lett. 2019 Jul 15;29(14):1779-1784. doi: 10.1016/j.bmcl.2019.05.010. Epub 2019 May 8.

Authors

Suresh Awale¹, Takahiro Okada², Dya Fita Dibwe³, Takahiro Maruyama², Satoyuki Takahara⁴, Takuya Okada⁴, Satoshi Endo⁵, Naoki Toyooka⁶

Affiliations

¹ 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.
² Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.
³ Division of Natural Drug Discovery, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
⁴ Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.
⁵ Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
⁶ Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan; Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan. Electronic address: toyooka@eng.u-toyama.ac.jp.

PMID: 31097375
DOI: 10.1016/j.bmcl.2019.05.010

Abstract

Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer cells' tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl)amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC₅₀ value of 0.44 μM, without exhibiting toxicity in normal, nutrient-rich medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.

Keywords: Antiausterity agent; Coumarin; Drug discovery; PANC-1; Pancreatic cancer; Preferential cytotoxicity.

Publication types

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

MeSH terms

Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Coumarins / chemical synthesis*
Coumarins / chemistry
Drug Discovery / methods*
Humans
Pancreatic Neoplasms / drug therapy*

Substances

Antineoplastic Agents
Coumarins