Tyrosol Derivatives, Bearing 3,5-Disubstituted Isoxazole and 1,4-Disubstituted Triazole, as Potential Antileukemia Agents by Promoting Apoptosis
Zaineb Abdelkafi-Koubaa,
Imen Aissa,
Hichem Ben Jannet,
Najet Srairi-Abid,
Naziha Marrakchi,
Samia Menif
Affiliations
Zaineb Abdelkafi-Koubaa
Laboratory of Biomolecules, Venoms and Theranostic Applications, LR20IPT01, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia
Imen Aissa
Team Medicinal Chemistry and Natural Products (LR11ES39), Laboratory of Heterocyclic, Chemistry, Natural Products and Reactivity, Department of Chemistry, Faculty of Science of Monastir, University of Monastir, Monastir 5019, Tunisia
Hichem Ben Jannet
Team Medicinal Chemistry and Natural Products (LR11ES39), Laboratory of Heterocyclic, Chemistry, Natural Products and Reactivity, Department of Chemistry, Faculty of Science of Monastir, University of Monastir, Monastir 5019, Tunisia
Najet Srairi-Abid
Laboratory of Biomolecules, Venoms and Theranostic Applications, LR20IPT01, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia
Naziha Marrakchi
Laboratory of Biomolecules, Venoms and Theranostic Applications, LR20IPT01, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia
Samia Menif
Molecular and Cellular Hematology Laboratory, LR16IPT07, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia
In the present study, we assess tyrosol derivatives bearing 3,5-disubstituted isoxazoles and 1,4-disubstituted triazoles for their ability to inhibit the proliferation of K562 cells derived from leukemia as well as primary chronic myeloid leukemia (CML) cells obtained from the peripheral blood of 15 CML patients including 10 patients with untreated chronic phase and 5 patients with resistance against imatinib or multiple TKI. Our results showed that most derivatives displayed significant anti-proliferative activity against K562 cells in a dose-dependent manner. Among them, compounds 3d and 4a exhibited greater potent anticancer activity with respective IC50 values of 16 and 18 µg/mL (45 µM and 61 µM). Interestingly, compound 3d inhibited CML cell proliferation not only in newly diagnosed but also in imatinib-resistant patients. We demonstrated that the anti-proliferative effect of this compound is mediated by a pro-apoptotic activity by promoting oxidative stress and modulating the activity of the Akt, p38 MAPK and Erk 1/2 pathways. In conclusion, our data highlight the potential of this class of derivative as a novel promising therapeutic agent for CML therapy.
