TY - JOUR
T1 - 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma
T2 - Synthesis, Cytotoxic Activity, and Inhibition of CDK1
AU - Carbone, Daniela
AU - Pecoraro, Camilla
AU - Panzeca, Giovanna
AU - Xu, Geng
AU - Roeten, Margot S. F.
AU - Cascioferro, Stella
AU - Giovannetti, Elisa
AU - Diana, Patrizia
AU - Parrino, Barbara
N1 - Funding Information: This work was partially supported by the following grants: PRIN2017, Prot. No. 2017E84AA4 and European Union 2014–2020 PON Ricerca e Innovazione grant from the Italian Ministry of Education, University and Research, entitled “INSAIL—Interventi a Supporto dello Sviluppo Avanzato, Integrato e Sostenibile dell’ Acquacultura” (ARS01_00934) to P.D. This research was also funded by KWF Dutch Cancer Society, grant number 11957, Cancer Center Amsterdam and Bennink Foundation, as well as by Associazione Italiana per la Ricerca sul Cancro (AIRC/IG-grant number 24444). We thank Cherien Ghandour (Master Oncology, VU University) for the technical assistance. Publisher Copyright: © 2023 by the authors.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - 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.
AB - 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.
KW - 1,3,4-oxadiazole
KW - 1,3,4-thiadiazole
KW - PDAC antiproliferative activity
KW - inhibition of CDK1 expression
KW - inhibition of migration
KW - nortopsentin analogs
UR - http://www.scopus.com/inward/record.url?scp=85166424201&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/md21070412
DO - https://doi.org/10.3390/md21070412
M3 - Article
C2 - 37504943
SN - 1660-3397
VL - 21
JO - Marine Drugs
JF - Marine Drugs
IS - 7
M1 - 412
ER -