Identification of New Small Molecules as Apoptosis Inhibitors in Vascular Endothelial Cells.

Vascular endothelial cell (VEC) apoptosis is involved in the development of atherosclerosis and other cardiovascular diseases. We previously found that ethyl 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole -5-carboxylate derivatives (3a-o) play important roles in cell fate control. In this study, among the 15 compounds, we further screened 2 compounds, 3d and 3k, that suppressed VEC apoptosis induced by deprivation of serum and fibroblast growth factor 2. To clarify which chiral enantiomers of 3d and 3k functioned, we synthesized 3d-S and its enantiomer 3d-R, 3k-S, and its enantiomer 3k-R. Then, we investigated the apoptosis-inhibiting activity of the chiral compounds in VECs. Four small molecules, 3d-S, 3d-R, 3k-S, 3k-R, significantly elevated VEC viability and inhibited apoptosis. Furthermore, these small molecules could obviously decrease the level of integrin β4 that plays a key role in the regulation of VEC apoptosis. 3k-S and 3k-R increased Bcl-2/Bax ratio and reduced reactive oxygen species levels dramatically. Therefore, we provide new VEC apoptosis inhibitors. These compounds may be potential agents in the prevention of vascular diseases associated with VEC apoptosis.