Amide and ester derivatives of chlorido[4-carboxy-1,2-disalicylideneaminobenzene]iron(iii) as necroptosis and ferroptosis inducers

Dalton Trans. 2020 May 26;49(20):6842-6853. doi: 10.1039/d0dt00168f.

Abstract

In continuation of the structure-activity study about 4-substituted chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(iii) complexes as necroptosis and ferroptosis inducers, we introduced a 4-COOH group at the 1,2-phenylenediamine moiety of the lead ([Fe(iii)salopheneCl]) and derived the resulting complex 15 to the respective ethyl, propyl, or butyl amides (16-18) and esters (19-21). The compounds 16-21 exerted concentration-dependent antiproliferative and antimetabolic effects against HL-60 cells. The esters were more active than the analogous amides. Elongation of the alkyl chain enhanced the activity of the amides, while that of the esters decreased. The complexes 16-21 induced necroptosis and/or ferroptosis but not apoptosis. Studies on protein binding and uptake into HL-60 cells indicated that the complexes mainly accumulated by passive transport. The high binding tendency of all complexes to apo-Transferrin, however, points to participation of a carrier-mediated transport into the cells, too.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology*
  • Ferroptosis / drug effects*
  • HL-60 Cells
  • Humans
  • Molecular Structure
  • Necroptosis / drug effects*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Amides
  • Antineoplastic Agents
  • Esters