Synthesis of Novel Nilotinib Analogues and Biological Evaluation of Their Antiplatelet Activity and Functionality towards Cancer Cell Proliferation In Vitro.

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.

Inflammation, Oxidative Stress, Vascular Aging and Atherosclerotic Ischemic Stroke.

Vascular aging is a crucial risk factor for atherosclerotic ischemic stroke. Vascular aging is characterized by oxidative stress, endothelial dysfunction, inflammation, intimal and media thickening, as well as the gradual development of arterial stiffness, among other pathophysiological features. Regarding oxidative stress, increased concentration of reactive oxygen and nitrogen species is linked to atherosclerotic ischemic stroke in vascular aging. Additionally, oxidative stress is associated with an inflammatory response. Inflammation is related to aging through the "inflammaging" theory, which is characterized by decreased ability to cope with a variety of stressors, in combination with an increased pro-inflammatory state. Vascular aging is correlated with changes in cerebral arteries that are considered predictors of the risk for atherosclerotic ischemic stroke. The aim of the present review is to present the role of oxidative stress and inflammation in vascular aging, as well as their involvement in atherosclerotic ischemic stroke.