2. Academic Validation
  3. Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents

Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents

  • Bioorg Med Chem Lett. 2020 Oct 1;30(19):127426. doi: 10.1016/j.bmcl.2020.127426.
Abdelmoula El Abbouchi 1,  Nabil El Brahmi 2,  Marie-Aude Hiebel 3,  Jérôme Bignon 4,  Gérald Guillaumet 1,  Franck Suzenet 3,  Saïd El Kazzouli 5
Affiliations

Affiliations

  • 1 Euromed Research Center, Euromed Institute of Technology, Euromed University of Fes (UEMF)-Route de Meknès, 30000 Fes, Morocco; Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, BP 6759, Orléans cedex 2 54067, France.
  • 2 Euromed Research Center, Euromed Institute of Technology, Euromed University of Fes (UEMF)-Route de Meknès, 30000 Fes, Morocco.
  • 3 Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, BP 6759, Orléans cedex 2 54067, France.
  • 4 Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, Gif-sur-Yvette, France.
  • 5 Euromed Research Center, Euromed Institute of Technology, Euromed University of Fes (UEMF)-Route de Meknès, 30000 Fes, Morocco. Electronic address: s.elkazzouli@ueuromed.org.
PMID: 32755677 DOI: 10.1016/j.bmcl.2020.127426
Abstract

A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 Cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of Cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC50 values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker's best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.

Keywords

Anti-cancer; Anti-proliferative; Cancer cells; Ethacrynic acid; Safety ratios; Sulfonamides.

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