Tyrosol Derivatives, Bearing 3,5-Disubstituted Isoxazole and 1,4-Disubstituted Triazole, as Potential Antileukemia Agents by Promoting Apoptosis

Abstract

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.

Calcium influx, oxidative stress, and apoptosis induced by TRPV1 in chronic myeloid leukemia cells: Synergistic effects with imatinib

“…On the other hand, the drug-induced oxidative stress exaggeration in leukemic cells could intensify the genotoxic effects of conventional therapy, facilitating the activation of programmed cell death ( Yang et al, 2018 ). In fact, recent findings showed that the stimulation of oxidative stress in CML, using compounds such as tyrosol derivatives, verbascoside, and zerumbone, promotes mitochondrial membrane potential dissipation, caspase activation, and apoptosis ( Rajan et al, 2015 ; Abdelkafi-Koubaa et al, 2022 ; Akgun-Cagliyan et al, 2022 ). Therefore, the strategy of deliberately increasing ROS to cytotoxic levels for leukemia cells seems to be very appealing, and our data are in agreement.…”

New Triazole-Isoxazole Hybrids as Antibacterial Agents: Design, Synthesis, Characterization, In Vitro, and In Silico Studies

“…Within this framework, the combination of biologically interesting core structural motifs [ 24 , 25 ], such as the triazole, with a further heterocyclic nucleus holds therapeutic properties in a variety of fields, including combating microbial pathogens [ 26 ]. Particularly, diversely substituted triazole/isoxazole conjugates have shown enhanced biological activities [ 27 , 28 , 29 ].…”