Early pharmacological profiling of isatin derivatives as potent and selective cytotoxic agents

Adrián Puerta, Aday González-Bakker, Pedro Brandão, Marta Pineiro, Anthony J. Burke, Elisa Giovannetti, Miguel X. Fernandes, José M. Padrón

Research output: Contribution to journalArticlepeer-review

Abstract

Isatin derivatives have attracted a lot of interest for their potential in the development of new anticancer drugs. A library of 38 isatin derivatives, created through an Ugi four-component reaction, underwent an initial screening in a panel of six human solid tumor cell lines. The four most active derivatives were then selected for further testing. These compounds showed selectivity towards the non-small cell lung cancer (NSCLC) cell line SW1573, whilst NSCLC A549 cells were barely affected. The combination of phenotypic assays, including wound healing, clonogenic and continuous live cell imaging provided a deeper understanding of the compounds’ mode of action. In particular, the latter demonstrated that isatin derivatives were able to induce necroptosis in SW1573 cells. The kinetics of cell death showed that necroptosis appeared after 2.5 h of exposure, which could be delayed to 7 h when co-treated with necrostatin-1. Interaction between the isatin derivatives and the KRAS G12C protein variant was discarded after in silico studies. Further studies are warranted to identify the cellular target responsible for the observed selectivity among cell lines.

Original languageEnglish
Article number116059
Pages (from-to)116059
JournalBiochemical Pharmacology
Volume222
DOIs
Publication statusPublished - Apr 2024

Keywords

  • Isatin
  • Live cell imaging
  • Necroptosis
  • Non-small cell lung cancer
  • Cell Proliferation
  • Carcinoma, Non-Small-Cell Lung
  • Humans
  • Structure-Activity Relationship
  • Lung Neoplasms
  • Cytotoxins
  • Antineoplastic Agents/pharmacology
  • Cell Line, Tumor
  • Molecular Structure
  • Isatin/pharmacology
  • Drug Screening Assays, Antitumor

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