Promotion of mammalian angiogenesis by neolignans derived from soybean extracellular fluids

Abstract

Excessive or insufficient angiogenesis is associated with major classes of chronic disease. Although less studied, small molecules which can promote angiogenesis are being sought as potential therapeutics for cardiovascular and peripheral arterial disease and stroke. Here we describe a bioassay-directed discovery approach utilising size exclusion and liquid chromatography to purify components of soybean xylem sap that have pro-angiogenic activity. Using high resolution accurate mass spectrometry and nuclear magnetic resonance spectroscopy, the structure of two pro-angiogenic molecules (FK1 and FK2) were identified as erythro-guaiacylglycerol-8-O-4'-(coniferyl alcohol) ether (eGGCE), and threo-guaiacylglycerol-8-O-4'-(coniferyl alcohol) ether (tGGCE). These two molecules, which are coniferyl neolignan stereoisomers, promoted in vitro angiogenesis in the μM to nM range. Independently sourced samples of eGGCE and tGGCE exhibited comparable pro-angiogenic activity to the soybean derived molecules. The cellular mode of action of these molecules was investigated by studying their effect on endothelial cell proliferation, migration, tube formation and adhesion to the extracellular matrix (ECM) components, fibronectin and vitronectin. They were found to enhance endothelial cell proliferation and endothelial cell tube formation on Matrigel, but did not affect endothelial cell migration or adhesion to fibronectin and vitronectin. Thus, this study has identified two coniferyl neolignan stereoisomers, eGGCE and tGGCE, as pro-angiogenic molecules, with eGGCE being less active than tGGCE.

Virtual Screening Based on Ligand and Structure with in vitro Assessment of Neolignans against Trypanosoma cruzi

“…7 As neolignans are a diverse group of chemical structures present in several plant families and responsible for multiple biological activities, we chose to investigate the trypanomicidal potential of a set of neolignans. [8][9][10][11] Some studies [12][13][14] have reported the importance of neolignans as promising compounds in the treatment against T. cruzi.…”

Developing Neolignans as Proangiogenic Agents: Stereoselective Total Syntheses and Preliminary Biological Evaluations of the Four Guaiacylglycerol 8-O-4′-Coniferyl Ethers

“… 1 Screening plant extracts for such properties is an emerging area of interest and the rat aortic ring model and related assays have proven useful in identifying natural products that can modulate angiogenesis. 2 , 3 By such means, various extracts of soybean (particularly the xylem sap) were evaluated recently, and two proangiogenic principals were isolated. 3 Although only small quantities of these materials were obtained, 1 H and 13 C NMR spectroscopic as well as mass spectral analyses suggested that these are one or other of the neolignans 1 or ent - 1 and 2 or ent - 2 .…”

“… 3 Although only small quantities of these materials were obtained, 1 H and 13 C NMR spectroscopic as well as mass spectral analyses suggested that these are one or other of the neolignans 1 or ent - 1 and 2 or ent - 2 . 3 The racemic forms of these compounds have previously been isolated from various other plant sources and shown to exhibit a range of biological effects. 4 They are almost certainly produced in vivo through peroxidase-mediated radical coupling of coniferyl alcohol, and optically enriched forms of them (but of undefined absolute stereochemistry) have been generated by enzymatic dehydrogenative coupling of this monomer using cell-free extracts of a producing organism.…”

“…Compounds that promote the formation of new blood vessels from existing endothelia are described as proangiogenic and could be beneficial in promoting wound healing, treating burns, and the revascularization of ischemic tissues encountered in stroke victims and those suffering from cardiac disorders . Screening plant extracts for such properties is an emerging area of interest and the rat aortic ring model and related assays have proven useful in identifying natural products that can modulate angiogenesis. , By such means, various extracts of soybean (particularly the xylem sap) were evaluated recently, and two proangiogenic principals were isolated . Although only small quantities of these materials were obtained, 1 H and 13 C NMR spectroscopic as well as mass spectral analyses suggested that these are one or other of the neolignans 1 or ent - 1 and 2 or ent - 2 .…”

“…Screening plant extracts for such properties is an emerging area of interest and the rat aortic ring model and related assays have proven useful in identifying natural products that can modulate angiogenesis. , By such means, various extracts of soybean (particularly the xylem sap) were evaluated recently, and two proangiogenic principals were isolated . Although only small quantities of these materials were obtained, 1 H and 13 C NMR spectroscopic as well as mass spectral analyses suggested that these are one or other of the neolignans 1 or ent - 1 and 2 or ent - 2 . The racemic forms of these compounds have previously been isolated from various other plant sources and shown to exhibit a range of biological effects .…”