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1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1

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 adenoc...

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Autores principales: Carbone, Daniela, Pecoraro, Camilla, Panzeca, Giovanna, Xu, Geng, Roeten, Margot S. F., Cascioferro, Stella, Giovannetti, Elisa, Diana, Patrizia, Parrino, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10381170/
https://www.ncbi.nlm.nih.gov/pubmed/37504943
http://dx.doi.org/10.3390/md21070412
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author Carbone, Daniela
Pecoraro, Camilla
Panzeca, Giovanna
Xu, Geng
Roeten, Margot S. F.
Cascioferro, Stella
Giovannetti, Elisa
Diana, Patrizia
Parrino, Barbara
author_facet Carbone, Daniela
Pecoraro, Camilla
Panzeca, Giovanna
Xu, Geng
Roeten, Margot S. F.
Cascioferro, Stella
Giovannetti, Elisa
Diana, Patrizia
Parrino, Barbara
author_sort Carbone, Daniela
collection PubMed
description 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 EC(50) 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.
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spelling pubmed-103811702023-07-29 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1 Carbone, Daniela Pecoraro, Camilla Panzeca, Giovanna Xu, Geng Roeten, Margot S. F. Cascioferro, Stella Giovannetti, Elisa Diana, Patrizia Parrino, Barbara Mar Drugs Article 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 EC(50) 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. MDPI 2023-07-19 /pmc/articles/PMC10381170/ /pubmed/37504943 http://dx.doi.org/10.3390/md21070412 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Carbone, Daniela
Pecoraro, Camilla
Panzeca, Giovanna
Xu, Geng
Roeten, Margot S. F.
Cascioferro, Stella
Giovannetti, Elisa
Diana, Patrizia
Parrino, Barbara
1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
title 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
title_full 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
title_fullStr 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
title_full_unstemmed 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
title_short 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
title_sort 1,3,4-oxadiazole and 1,3,4-thiadiazole nortopsentin derivatives against pancreatic ductal adenocarcinoma: synthesis, cytotoxic activity, and inhibition of cdk1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10381170/
https://www.ncbi.nlm.nih.gov/pubmed/37504943
http://dx.doi.org/10.3390/md21070412
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