Simple 2(5H)-furanone derivatives with selective cytotoxicity towards non-small cell lung cancer cell line A549 - Synthesis, structure-activity relationship and biological evaluation

Anna Byczek-Wyrostek; Radoslaw Kitel; Klaudia Rumak; Magdalena Skonieczna; Anna Kasprzycka; Krzysztof Walczak

doi:10.1016/j.ejmech.2018.03.021

Simple 2(5H)-furanone derivatives with selective cytotoxicity towards non-small cell lung cancer cell line A549 - Synthesis, structure-activity relationship and biological evaluation

Eur J Med Chem. 2018 Apr 25:150:687-697. doi: 10.1016/j.ejmech.2018.03.021. Epub 2018 Mar 10.

Authors

Anna Byczek-Wyrostek¹, Radoslaw Kitel², Klaudia Rumak³, Magdalena Skonieczna⁴, Anna Kasprzycka⁵, Krzysztof Walczak⁵

Affiliations

¹ Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego Street 4, 44-100, Gliwice, Poland; Centre of Biotechnology, Silesian University of Technology, Krzywoustego Street 8, 44-100, Gliwice, Poland. Electronic address: anna.byczek-wyrostek@polsl.pl.
² Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego Street 4, 44-100, Gliwice, Poland; Centre of Biotechnology, Silesian University of Technology, Krzywoustego Street 8, 44-100, Gliwice, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa Street 7a, 30-387, Krakow, Poland; Department of Organic Chemistry, Jagiellonian University, Ingardena Street 3, 30-060, Krakow, Poland.
³ Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego Street 4, 44-100, Gliwice, Poland.
⁴ Centre of Biotechnology, Silesian University of Technology, Krzywoustego Street 8, 44-100, Gliwice, Poland; Biosystems Group, Institute of Automatic Control, Silesian University of Technology, Akademicka Street 16, 44-100, Gliwice, Poland.
⁵ Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego Street 4, 44-100, Gliwice, Poland; Centre of Biotechnology, Silesian University of Technology, Krzywoustego Street 8, 44-100, Gliwice, Poland.

PMID: 29571156
DOI: 10.1016/j.ejmech.2018.03.021

Abstract

A series of 5-alkoxy derivatives of 3,4-dichloro-5-hydroxyfuran-2-(5H)-one (mucochloric acid, MCA) were obtained and subsequently subjected to modification in the C-4 position of 2(5H)-furanone ring. The cytotoxicity of newly synthesized compounds was evaluated in MTT assay against non-small cell lung cancer (A549) and healthy lung epithelial cell line (BEAS-2B). The derivatives containing a branched alkoxy substituent in the C-5 position demonstrated the highest anticancer properties, whereas modification of compounds in the C-4 position of 2(5H)-furanone ring only slightly improve their antiproliferative properties. Compounds 12 and 15 exhibited the best selectivity towards A549 cells and were also evaluated in a panel of cancer cell lines of different origin. Further investigation revealed that treatment of A549 cell line with compounds 12 and 15 led to G2 phase cell cycle arrest and induction of caspase-independent cell death. Moreover, compound 12 was found to act synergistically with erlotinib.

Keywords: 2(5H)-Furanone; Anticancer activity; Cells dead; Nucleophilic substitution.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Cycle Checkpoints / drug effects
Cell Death / drug effects
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Furans / chemical synthesis
Furans / chemistry
Furans / pharmacology*
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Furans
mucochloric acid