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

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.
Stella Cascioferro 1,  Giovanna Li Petri 2,  Barbara Parrino 1,  Daniela Carbone 1,  Niccola Funel 3,  Cecilia Bergonzini 4,  Giulia Mantini 4,  Henk Dekker 4,  Daan Geerke 5,  Godefridus J Peters 4,  Girolamo Cirrincione 1,  Elisa Giovannetti 6,  Patrizia Diana 7
Affiliations

Affiliations

  • 1 Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
  • 2 Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy; Department of Medical Oncology, Amsterdam University Medical Center, VU University Cancer Center Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, the Netherlands.
  • 3 Unit of Anatomic Pathology II, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126, Pisa, Italy.
  • 4 Department of Medical Oncology, Amsterdam University Medical Center, VU University Cancer Center Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, the Netherlands.
  • 5 AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands.
  • 6 Department of Medical Oncology, Amsterdam University Medical Center, VU University Cancer Center Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Via Ferruccio Giovannini 13, 56017, San Giuliano Terme, Pisa, Italy. Electronic address: e.giovannetti@amsterdamumc.nl.
  • 7 Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy. Electronic address: patrizia.diana@unipa.it.
PMID: 32007666 DOI: 10.1016/j.ejmech.2020.112088
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.

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