Structure-activity relationships of saponins enhancing the cytotoxicity of ribosome-inactivating proteins type I (RIP-I).

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.