Abstract
In this work, we designed and synthesized a series of amide derivatives (1–13), benzoxazine derivatives (16–28) and amino derivatives (29–30) from xyloketal B. All 28 new derivatives and seven known compounds (14, 15, 31–35) were evaluated for their protection against H2O2-induced HUVEC injury. 23 and 24 exhibited more potential protective activities than other derivatives; and the EC50 values of them and the leading compound 31 (xyloketal B) were 5.10, 3.59 and 15.97 μM, respectively. Meanwhile, a comparative molecular similarity indices analysis (CoMSIA) was constructed to explain the structural activity relationship of these xyloketal derivatives. This 3D QSAR model from CoMSIA suggested that the derived model exhibited good predictive ability in the external test-set validation. Derivative 24 fit well with the COMSIA map, therefore it possessed the highest activity of all compounds. Compounds 23, 24 and 31 (xyloketal B) were further to examine in the JC-1 mitochondrial membrane potential (MMP) assay of HUVECs using flow cytometry (FCM). The result indicated that 23 and 24 significantly inhibited H2O2-induced decrease of the cell mitochondrial membrane potential (ΔΨm) at 25 μM. Collectively, the protective effects of xyloketals on H2O2-induced endothelial cells may be generated from oxidation action by restraining ROS and reducing the MMP.
Highlights
Cardiovascular disease (CVD) has drawn significant attention in recent years because it has become the leading cause of mortality worldwide, affecting people from every income level
We previously demonstrated that xyloketal B has protective action against a variety of pathophysiological stimuli, such as oxLDL, oxygen-glucose deprivation (OGD) and 1-methyl-4-phenylpyridinium (MPP+), in different disease models [13,14,15,16,17,18]
All the new compounds were prepared from xyloketal B and xyloketal B acid that were gained from synthetic way in the ordinary state without any asymmetric factors [16]
Summary
Cardiovascular disease (CVD) has drawn significant attention in recent years because it has become the leading cause of mortality worldwide, affecting people from every income level. Reactive oxygen species (ROS), including H2O2, OH−, NO, and ONOO−, play key roles in the pathogenesis of many. The ROS-induced oxidative stress in cardiac and vascular is closely connected with the endothelial dysfunction in disease initiation and progression. Reactive oxygen species (ROS) are generated under pathological conditions, such as ischemia-reperfusion and inflammation, and activate pro-apoptotic and anti-apoptotic signaling programs in endothelial cells [1]. As one of the most common ROS, hydrogen peroxide (H2O2) can cross the plasma membrane, produce a highly reactive radical OH·, and lead to cell and tissue damage [2,3]. The generation of H2O2 plays a key role in the atherosclerotic progression. As the major type of endothelial cells, human umbilical vein endothelial cells (HUVECs) are commonly accepted as a model cell to explore the mechanisms involved in the pathogenesis of CVDs [8]
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