Targeting microtubule dynamics: synthesis and evaluation of novel 4-thiazolidinone derivatives in pancreatic Cancer
Abstract
Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and high chemoresistance partly associated with β-tubulin overexpression. In this study, we synthesized and biologically evaluated a series of 4-thiazolidinone derivatives, identifying Les-6666 and Les-5549 as potent anticancer candidates. An optimized microwave-assisted synthetic protocol enabled efficient and environmentally friendly production of selected derivatives. In silico ADMET profiling predicted favorable drug-like properties, high gastrointestinal absorption, and no blood–brain barrier penetration. Molecular docking studies revealed strong binding affinity of selected compounds to the colchicine and combretastatin A4 (CA4) sites of β-tubulin. Biological evaluation through the NCI-60 screening program demonstrated pronounced antiproliferative activity, with Les-6666 exhibiting submicromolar GI50 values across multiple cancer cell lines. In pancreatic MIA PaCa-2 cells, both Les-6666 and Les-5549 showed potent cytotoxicity (IC50 = 0.08 μM and 0.10 μM, respectively), inhibited DNA synthesis, suppressed clonogenic survival, reduced migration, arrested cells at the G2/M phase of the cell cycle and induced apoptosis. Tubulin polymerization assays confirmed significant depolymerizing activity comparable to CA4. Furthermore, Les-6666 reduced β-tubulin protein expression, consistent with tubulin autoregulatory feedback mechanisms. Collectively, these findings identify Les-6666 as a promising antiproliferative agent that inhibits tubulin polymerization in pancreatic cancer cells warranting further investigation.
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BibTeX
@article{dudchak2026targeting,
title = {{Targeting microtubule dynamics: synthesis and evaluation of novel 4-thiazolidinone derivatives in pancreatic Cancer}},
author = {Rostyslav Dudchak and Serhii Holota and Magdalena Podolak and Olga Klaudia Szewczyk-Roszczenko and Ihor Yushyn and Nazar Solodyak and Olexandr Karpenko and Robert Czarnomysy and Agnieszka Gornowicz and Małgorzata Borzym-Kluczyk and Yegor Vassetzky and Anna Bielawska and Krzysztof Bielawski and Roman Lesyk},
journal = {Bioorganic Chemistry},
year = {2026},
month = jun,
doi = {10.1016/j.bioorg.2026.110149},
url = {https://hal.science/hal-05760420v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting microtubule dynamics: synthesis and evaluation of novel 4-thiazolidinone derivatives in pancreatic Cancer
AU - Rostyslav Dudchak
AU - Serhii Holota
AU - Magdalena Podolak
AU - Olga Klaudia Szewczyk-Roszczenko
AU - Ihor Yushyn
AU - Nazar Solodyak
AU - Olexandr Karpenko
AU - Robert Czarnomysy
AU - Agnieszka Gornowicz
AU - Małgorzata Borzym-Kluczyk
AU - Yegor Vassetzky
AU - Anna Bielawska
AU - Krzysztof Bielawski
AU - Roman Lesyk
PY - 2026
DA - 2026/06/22
JO - Bioorganic Chemistry
DO - 10.1016/j.bioorg.2026.110149
UR - https://hal.science/hal-05760420v1
AB - Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and high chemoresistance partly associated with β-tubulin overexpression. In this study, we synthesized and biologically evaluated a series of 4-thiazolidinone derivatives, identifying Les-6666 and Les-5549 as potent anticancer candidates. An optimized microwave-assisted synthetic protocol enabled efficient and environmentally friendly production of selected derivatives. In silico ADMET profiling predicted favorable drug-like properties, high gastrointestinal absorption, and no blood–brain barrier penetration. Molecular docking studies revealed strong binding affinity of selected compounds to the colchicine and combretastatin A4 (CA4) sites of β-tubulin. Biological evaluation through the NCI-60 screening program demonstrated pronounced antiproliferative activity, with Les-6666 exhibiting submicromolar GI50 values across multiple cancer cell lines. In pancreatic MIA PaCa-2 cells, both Les-6666 and Les-5549 showed potent cytotoxicity (IC50 = 0.08 μM and 0.10 μM, respectively), inhibited DNA synthesis, suppressed clonogenic survival, reduced migration, arrested cells at the G2/M phase of the cell cycle and induced apoptosis. Tubulin polymerization assays confirmed significant depolymerizing activity comparable to CA4. Furthermore, Les-6666 reduced β-tubulin protein expression, consistent with tubulin autoregulatory feedback mechanisms. Collectively, these findings identify Les-6666 as a promising antiproliferative agent that inhibits tubulin polymerization in pancreatic cancer cells warranting further investigation.
SN - 0045-2068
SN - 1090-2120
ER -