Pechlivani Louisa, Ntemou Nikoleta, Pantazi Despoina, Alivertis Dimitrios, Skobridis Konstantinos, Tselepis Alexandros D
Atherothrombosis Research Centre, Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece.
Pharmaceuticals (Basel). 2024 Mar 7;17(3):349. doi: 10.3390/ph17030349.
Nilotinib, a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia (CML), inhibits Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells, as well as other malignancies. In the present study, new nilotinib analogues were synthesized and fully characterized. A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated. The expression and antimetastatic effects of E-cadherin and N-cadherin were assessed. The analogues inhibited platelet aggregation in a statistically significant manner compared to nilotinib, while they exhibited a strong inhibitory effect on P-selectin and PAC-1 expression when activated by AA. All three analogues caused arrest in the mitosis phase of the HepG2 cell cycle, while analogue-1 exhibited the most potent apoptotic effect compared to nilotinib. Interestingly, none of them promoted apoptosis in HUVECs. All the analogues reduced the expression of E- and N-cadherin in different amounts, while the analogues-1 and -3 exhibited similar antimigratory effects on HepG2 cells. The results of this study reveal considerable potential to develop new tyrosine kinase inhibitors with improved antiplatelet and antitumor properties.
尼罗替尼是一种用于治疗慢性粒细胞白血病（CML）的第二代酪氨酸激酶抑制剂，可抑制Bcr-Abl酪氨酸激酶活性以及表达Bcr-Abl的细胞和其他恶性肿瘤细胞的增殖。在本研究中，合成了新型尼罗替尼类似物并对其进行了全面表征。进行了血小板聚集试验，并评估了P-选择素和PAC-1的表达以及对健康内皮细胞增殖的影响。评估了E-钙黏蛋白和N-钙黏蛋白的表达及抗转移作用。与尼罗替尼相比，这些类似物以具有统计学意义的方式抑制血小板聚集，同时在被花生四烯酸（AA）激活时，它们对P-选择素和PAC-1的表达表现出强烈的抑制作用。所有三种类似物均导致HepG2细胞周期的有丝分裂期停滞，而与尼罗替尼相比，类似物-1表现出最强的凋亡作用。有趣的是，它们均未促进人脐静脉内皮细胞（HUVECs）凋亡。所有类似物均不同程度地降低了E-钙黏蛋白和N-钙黏蛋白的表达，而类似物-1和-3对HepG2细胞表现出相似的抗迁移作用。本研究结果显示，开发具有改善的抗血小板和抗肿瘤特性的新型酪氨酸激酶抑制剂具有巨大潜力。
