Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

Eur J Med Chem. 2020 Mar 1;189:112088. doi: 10.1016/j.ejmech.2020.112088. Epub 2020 Jan 25.

Abstract

A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29-12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.

Keywords: Antiproliferative activity; Imidazo[2,1-b][1,3,4]thiadiazole derivatives; Inhibition of migration; Modulation of EMT; PTK2/FAK; Pancreatic ductal adenocarcinoma; Spheroids shrinkage.

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Movement
  • Cell Proliferation
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism*
  • Epithelial-Mesenchymal Transition
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Thiadiazoles / chemistry*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Thiadiazoles
  • Thiophenes
  • Deoxycytidine
  • gemcitabine