1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
Daniela Carbone,
Camilla Pecoraro,
Giovanna Panzeca,
Geng Xu,
Margot S. F. Roeten,
Stella Cascioferro,
Elisa Giovannetti,
Patrizia Diana,
Barbara Parrino
Affiliations
Daniela Carbone
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Camilla Pecoraro
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Giovanna Panzeca
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Geng Xu
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Margot S. F. Roeten
Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Stella Cascioferro
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Elisa Giovannetti
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Patrizia Diana
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Barbara Parrino
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
A new series of nortopsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,3,4-oxadiazole or 1,3,4-thiadiazole moiety, was efficiently synthesized. The antiproliferative activity of all synthesized derivatives was evaluated against five pancreatic ductal adenocarcinoma (PDAC) cell lines, a primary culture and a gemcitabine-resistant variant. The five more potent compounds elicited EC50 values in the submicromolar–micromolar range, associated with a significant reduction in cell migration. Moreover, flow cytometric analysis after propidium iodide staining revealed an increase in the G2-M and a decrease in G1-phase, indicating cell cycle arrest, while a specific ELISA demonstrated the inhibition of CDK1 activity, a crucial regulator of cell cycle progression and cancer cell proliferation.
