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A series of glucal-conjugated sterols as novel vascular leakage blocker were identified through design, synthesis and biologically evaluation. In addition, the structure-activity relationship (SAR) of the glucal-conjugated sterols focusing on the C17-side chain was also established. The sterol analogs linked with the rigid C17-side chain side chains exhibited potent cell survival activities. In particular, analog 21l, which possesses a cyclopentyl oxime moiety, was shown to have excellent pharmacological effects on retinal vascular leakage in a diabetic mouse model., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Highlights: [•] We developed a novel vascular leakage blocker Sac-1004 on basis of cell based assay. [•] Sac-1004 prevents VEGF, thrombin and histamine induced endothelial permeability. [•] Sac-1004 stabilized adherens and tight junctions in endothelial cells. [•] Sac-1004 protects endothelial barrier integrity via cAMP induction and Rac activation. [•] Sac-1004 phosphorylates cortactin and induces cortical actin ring formation. [ABSTRACT FROM AUTHOR]

Endothelial barrier integrity is essential for vascular homeostasis and increased vascular permeability and has been implicated in many pathological processes, including diabetic retinopathy. Here, we investigated the effect of Rk1, a ginsenoside extracted from sun ginseng, on regulation of endothelial barrier function. In human retinal endothelial cells, Rk1 strongly inhibited permeability induced by VEGF, advanced glycation end-product, thrombin, or histamine. Furthermore, Rk1 significantly reduced the vessel leakiness of retina in a diabetic mouse model. This anti-permeability activity of Rk1 is correlated with enhanced stability and positioning of tight junction proteins at the boundary between cells. Signaling experiments revealed that Rk1 induces phosphorylation of myosin light chain and cortactin, which are critical regulators for the formation of the cortical actin ring structure and endothelial barrier. These findings raise the possibility that ginsenoside Rk1 could be exploited as a novel prototype compound for the prevention of human diseases that are characterized by vascular leakage. [ABSTRACT FROM AUTHOR]