Activity of Fluoro-Substituted 3,5-Di[(E)-Benzylidene]piperidin-4-Ones with N-Arylsulfonyl Appendages Against KRAS-Mutant Pancreatic Ductal Adenocarcinoma Cells
- 1Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
- 2Organic Chemistry 1, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany
Abstract
KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality that still lacks efficient therapies. Monoketone-based bisarylidene curcuminoid derivatives have shown promising activities against various PDAC models. Based on our previous findings on anticancer-active N-acryloyl-modified piperidin-4-one derivatives, we replaced the reactive acryloyl moiety by a series of N-arylsulfonyl bis-difluoro/trifluoromethylbenzylidene piperidin-4-one derivatives and tested them for antiproliferative activity against KRAS-mutant PDAC cells. Furthermore, apoptosis induction based on caspase-3/7 activation and STAT3 inhibition were investigated for the most promising compound. Notably, the N-tosyl derivative 3a with 4-trifluoromethyl substituents at the benzylidene rings exhibited the highest antiproliferative activities against PDAC cells (IC50 = 0.22–0.26 µM, 48 h). Derivative 3a also strongly induced apoptosis in PDAC cells and suppressed STAT3 activation/phosphorylation, which was supported by molecular docking of this curcuminoid into the SH2 domain of STAT3 and by 3a-STAT3 binding confirmed using CETSA in MiaPaCa-2 cells. These findings identify compound 3a as a promising lead for further preclinical evaluation in KRAS-mutant PDAC models and in other STAT3-dependent cancer types.
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BibTeX
@article{ghosh2026activity,
title = {{Activity of Fluoro-Substituted 3,5-Di[(E)-Benzylidene]piperidin-4-Ones with N-Arylsulfonyl Appendages Against KRAS-Mutant Pancreatic Ductal Adenocarcinoma Cells}},
author = {Hindole Ghosh and Duha Qamar Azaz and Addhyan Saxena and Nicole Bodenhausen and Rainer Schobert and Bernhard Biersack and Prasad Dandawate},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272110013},
url = {https://www.mdpi.com/1422-0067/27/21/10013},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Activity of Fluoro-Substituted 3,5-Di[(E)-Benzylidene]piperidin-4-Ones with N-Arylsulfonyl Appendages Against KRAS-Mutant Pancreatic Ductal Adenocarcinoma Cells
AU - Hindole Ghosh
AU - Duha Qamar Azaz
AU - Addhyan Saxena
AU - Nicole Bodenhausen
AU - Rainer Schobert
AU - Bernhard Biersack
AU - Prasad Dandawate
PY - 2026
DA - 2026/11/08
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272110013
UR - https://www.mdpi.com/1422-0067/27/21/10013
AB - KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality that still lacks efficient therapies. Monoketone-based bisarylidene curcuminoid derivatives have shown promising activities against various PDAC models. Based on our previous findings on anticancer-active N-acryloyl-modified piperidin-4-one derivatives, we replaced the reactive acryloyl moiety by a series of N-arylsulfonyl bis-difluoro/trifluoromethylbenzylidene piperidin-4-one derivatives and tested them for antiproliferative activity against KRAS-mutant PDAC cells. Furthermore, apoptosis induction based on caspase-3/7 activation and STAT3 inhibition were investigated for the most promising compound. Notably, the N-tosyl derivative 3a with 4-trifluoromethyl substituents at the benzylidene rings exhibited the highest antiproliferative activities against PDAC cells (IC50 = 0.22–0.26 µM, 48 h). Derivative 3a also strongly induced apoptosis in PDAC cells and suppressed STAT3 activation/phosphorylation, which was supported by molecular docking of this curcuminoid into the SH2 domain of STAT3 and by 3a-STAT3 binding confirmed using CETSA in MiaPaCa-2 cells. These findings identify compound 3a as a promising lead for further preclinical evaluation in KRAS-mutant PDAC models and in other STAT3-dependent cancer types.
SN - 1422-0067
ER -