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

Naturally-occurring 3 beta -O-chacotriosides of solasodine (solamargine), o f its 22S, 25S isomer tomatidenol (beta -solamarine), and of solanidine (ch aconine), as well as ring E- and F-modified derivatives of solamargine were prepared and assayed in order to assess the relevance of aglycone structur al features to membrane-disruption and enzyme-inhibitory activities of the related glycoalkaloids. A rings E-opened dihydro-derivative of solasodine ( the chacotrioside of dihydrosolasodine A) did not bind to cholesterol, stig masterol or ergosterol in vitro, disrupt PC/cholesterol liposomes or mammal ian erythrocytes, or inhibit acetylcholinesterase in vitro. It did not syne rgise with the solatrioside of dihydrosolasodine A or solasonine (nor did s olamargine with dihydrosolasodine A solatrioside) in haemolysis tests. The ring F modified derivative, N-nitrososolamargine, did not inhibit acetylcho linesterase in vitro, but lysed liposomes at greater than or equal to 150 m uM 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-acetylcholinestera se activity in vitro at up to 100 muM, but disrupted liposomes at 75 and 15 0 muM, although not to the extent caused by solamargine or chaconine. In co mbination with both the (inactive) solatriosides, solasonine and solanine, 75 muM beta -solamarine produced synergistic effects, with liposome disrupt ion greater than 150 muM beta -solamarine alone, beta -Solamarine, solamarg ine and chaconine showed similar haemolytic activity. beta -Solamarine syne rgised with the solatriosides solasonine and solanine in disrupting erythro cytes. Preliminary structure-activity relationships were evaluated for the active chacotriosides in an attempt to define the scope and limitations of this model study. (C) 2001 Elsevier Science Ltd. All rights reserved.