Design, synthesis, and in vitro antiproliferative evaluation of dasatinib/HO-1 inhibitor codrugs towards glioblastoma therapy.
4 affiliations
- 1Department of Drug and Health Sciences, University of Catania viale A. Doria 6 95125 Catania Italy [email protected] +39 095 738 4053.
- 2Department of Pharmacy, "Federico II" University of Naples 80131 Naples Italy.
- 3Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology Giza 12587 Egypt.
- 4Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia 41522 Egypt.
Abstract
Herein, dasatinib (DASA) and heme oxygenase-1 (HO-1) inhibitor codrugs were designed and synthesized. Derivatization of DASA was performed by preserving the structural features essential for target inhibition and was rationally guided by molecular modelling studies. Two out of three synthesized codrugs showed the ability to inhibit HO-1 activity in a low micromolar range (i.e., 2.12 and 1.00 μM for TC7 and TC8, respectively), while all derivatives retained a significant capability of inhibiting the cSRC tyrosine kinase with sub-micromolar potency (i.e., 0.0023-0.0255 μM). Of note, derivative TC7 exhibited significant in vitro antiproliferative activity against U87MG glioblastoma cells, likely mediated by HO inhibition and accompanied by a ∼1.5-fold increase in intracellular ROS levels compared with the control. Also, assessment of the most promising codrug, TC7, revealed high chemical and enzymatic stability (t 1/2 >24 h). While additional optimization will be required to further improve its drug-like profile, TC7 emerged as the most promising compound evaluated in this study and represents a suitable starting point for future development. Collectively, these results serve as a proof of concept supporting a potential new codrugs strategy combining HO-1 and cSRC inhibition for glioblastoma therapy.
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BibTeX
@article{pittala2026design,
title = {{Design, synthesis, and in vitro antiproliferative evaluation of dasatinib/HO-1 inhibitor codrugs towards glioblastoma therapy.}},
author = {Valeria Pittalà and Loredana Salerno and Valeria Consoli and Agata Grazia D'Amico and Valeria Sorrenti and Luca Vanella and Giorgia Centamore and Chiara Terlati and Sara Mocka and Maria Nunziata Modica and Giuseppe Romeo and Marica Erminia Schiano and Federica Sodano and Mohamed A Helal and Sebastiano Intagliata},
journal = {RSC medicinal chemistry},
year = {2026},
month = oct,
doi = {10.1039/d6md00227g},
url = {https://europepmc.org/article/MED/42910035},
note = {CC BY},
}
RIS
TY - JOUR
TI - Design, synthesis, and in vitro antiproliferative evaluation of dasatinib/HO-1 inhibitor codrugs towards glioblastoma therapy.
AU - Valeria Pittalà
AU - Loredana Salerno
AU - Valeria Consoli
AU - Agata Grazia D'Amico
AU - Valeria Sorrenti
AU - Luca Vanella
AU - Giorgia Centamore
AU - Chiara Terlati
AU - Sara Mocka
AU - Maria Nunziata Modica
AU - Giuseppe Romeo
AU - Marica Erminia Schiano
AU - Federica Sodano
AU - Mohamed A Helal
AU - Sebastiano Intagliata
PY - 2026
DA - 2026/10/07
JO - RSC medicinal chemistry
DO - 10.1039/d6md00227g
UR - https://europepmc.org/article/MED/42910035
AB - Herein, dasatinib (DASA) and heme oxygenase-1 (HO-1) inhibitor codrugs were designed and synthesized. Derivatization of DASA was performed by preserving the structural features essential for target inhibition and was rationally guided by molecular modelling studies. Two out of three synthesized codrugs showed the ability to inhibit HO-1 activity in a low micromolar range (i.e., 2.12 and 1.00 μM for TC7 and TC8, respectively), while all derivatives retained a significant capability of inhibiting the cSRC tyrosine kinase with sub-micromolar potency (i.e., 0.0023-0.0255 μM). Of note, derivative TC7 exhibited significant in vitro antiproliferative activity against U87MG glioblastoma cells, likely mediated by HO inhibition and accompanied by a ∼1.5-fold increase in intracellular ROS levels compared with the control. Also, assessment of the most promising codrug, TC7, revealed high chemical and enzymatic stability (t 1/2 >24 h). While additional optimization will be required to further improve its drug-like profile, TC7 emerged as the most promising compound evaluated in this study and represents a suitable starting point for future development. Collectively, these results serve as a proof of concept supporting a potential new codrugs strategy combining HO-1 and cSRC inhibition for glioblastoma therapy.
SN - 2632-8682
ER -