title: Structure-activity relationships of saponins enhancing the cytotoxicity of ribosome-inactivating proteins type I (RIP-I).
abstract: Saponins are amphiphilic secondary plant compounds able to interfere with surfaces and permeabilize membranes. In addition to antimicrobial and anti-inflammatory features, anti-neoplastic activities are described which base on various mechanisms. A very promising anti-cancer strategy is the synergistic enhancement of the cytotoxicity of ribosome-inactivating proteins type I (RIP-I) by suitable saponins. The cytotoxicity of the naturally low cytotoxic activity showing RIP-I can be augmented up to 100,000-fold, if they are applied in combination with appropriate saponins. These saponins have to hold certain structural features. We analyzed 56 different saponins for their non-synergistic, as well as their synergistic cytotoxicity with the RIP-I saporin from Saponaria officinalis L. (Caryophyllaceae). The saponins were assorted into categories, according to their structural features and their cytotoxic behavior, to build up structure-activity relationships. A non-synergistic cytotoxicity as low as possible and a synergistic cytotoxicity as high as possible were desired. The investigations suggest that ideal saponins consist of an oleanane-type scaffold, preferably gypsogenin or quillaic acid, three branched sugars at the C-3-OH-group including glucuronic acid, galactose, xylose and four branched sugars at the C-28-OH-group, including deoxy-sugars and acetyl-residues.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böttger
authors.forename: Elena
authors.initials: E
authors.lastname: Westhof
authors.forename: Karsten
authors.initials: K
authors.lastname: Siems
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Melzig
mesh_terms: D045744:Cell Line, Tumor; D003124:Colorimetry; D004847:Epithelial Cells / Q000378:metabolism*; D005453:Fluorescence; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D054789:Ribosome Inactivating Proteins, Type 1 / Q000378:metabolism* / Q000633:toxicity*; D012503:Saponins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D054789:Ribosome Inactivating Proteins, Type 1; D012503:Saponins; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue
keywords: Cytotoxicity; Protein toxin; RIP; SAR; Saponin; Synergistic