Laboratory of Biomolecules, Venoms and Theranostic Applications, LR20IPT01, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia.
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.
Molecules. 2022 Aug 10;27(16):5086. doi: 10.3390/molecules27165086.
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 and exhibited greater potent anticancer activity with respective IC values of 16 and 18 µg/mL (45 µM and 61 µM). Interestingly, compound 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.
在本研究中，我们评估了带有 3,5-二取代异恶唑和 1,4-二取代三唑的酪醇衍生物抑制白血病衍生的 K562 细胞以及从 15 名 CML 患者的外周血获得的原发性慢性髓系白血病（CML）细胞增殖的能力，其中包括 10 名未经治疗的慢性期患者和 5 名对伊马替尼或多种 TKI 耐药的患者。我们的结果表明，大多数衍生物以剂量依赖的方式对 K562 细胞表现出显著的抗增殖活性。其中，化合物 和 表现出更强的抗癌活性，各自的 IC 值为 16 和 18 µg/mL（45 µM 和 61 µM）。有趣的是，化合物 不仅抑制新诊断的 CML 患者，而且抑制伊马替尼耐药患者的 CML 细胞增殖。我们证明该化合物的抗增殖作用是通过促进氧化应激和调节 Akt、p38 MAPK 和 Erk 1/2 通路的活性来介导的促凋亡活性。总之，我们的数据强调了这类衍生物作为 CML 治疗的新型有前途的治疗剂的潜力。
