Membrane disruption and enzyme inhibition by naturally-occurring and modified chacotriose-containing Solanum steroidal glycoalkaloids.

Naturally-occurring 3beta-O-chacotriosides of solasodine (solamargine), of its 22S, 25S isomer tomatidenol (beta-solamarine), and of solanidine (chaconine), as well as ring E- and F-modified derivatives of solamargine were prepared and assayed in order to assess the relevance of aglycone structural features to membrane-disruption and enzyme-inhibitory activities of the related glycoalkaloids. A ring E-opened dihydro-derivative of solasodine (the chacotrioside of dihydrosolasodine A) did not bind to cholesterol, stigmasterol or ergosterol in vitro, disrupt PC/cholesterol liposomes or mammalian erythrocytes. or inhibit acetylcholinesterase in vitro. It did not synergise with the solatrioside of dihydrosolasodine A or solasonine (nor did solamargine with dihydrosolasodine A solatrioside) in haemolysis tests. The ring F modified derivative, N-nitrososolamargine, did not inhibit acetylcholinesterase in vitro, but lysed liposomes at > or = 150 microM and pH 7. Increasing the pH to 8 (but not 9) further enhanced disruption. The combination of N-nitrososolamargine and solasonine did not cause any disruption of liposomes. Beta-solamarine showed no anti-acetylcholinesterase activity in vitro at up to 100 microM, but disrupted liposomes at 75 and 150 microM, although not to the extent caused by solamargine or chaconine. In combination with both the (inactive) solatriosides, solasonine and solanine, 75 microM beta-solamarine produced synergistic effects, with liposome disruption greater than 150 microM beta-solamarine alone. Beta-solamarine, solamargine and chaconine showed similar haemolytic activity. Beta-solamarine synergised with the solatriosides solasonine and solanine in disrupting erythrocytes. Preliminary structure-activity relationships were evaluated for the active chacotriosides in an attempt to define the scope and limitations of this model study.