Inhibition of S-adenosyl-L-methionine sterol-C-24-methyltransferase by analogues of a carbocationic ion high-energy intermediate. Structure activity relationships for C-25 heteroatoms (N, As, S) substituted triterpenoid derivatives.

摘要: Microsomes from maize seedlings are capable of catalyzing the C-24 alkylation 4,4,14 alpha-trimethyl-9 beta,19-cyclo-5 alpha-cholest-24-en-3 beta-ol (cycloartenol) by (S)-adenosyl-L-methionine (AdoMet) leading to 24-methylene cycloartanol. Derivatives cycloartenol bearing a nitrogen atom at C-25 have been previously shown be potent inhibitors AdoMet-cycloartenol-C-24-methyltransferase (Narula, A. S., Rahier, A., Benveniste, P., and Schuber, F. (1981) J. Am. Chem. Soc. 103, 2408-2409). In order determine molecular parameters inhibition gain information about its mechanism, various azasteroids analogues synthesized assayed. The following results obtained. i) presence positive charge position 25 was found major cause since electrostatically neutral isosteric compounds possessing carbon in place were not inhibitory. may conferred protonated amine, quaternary ammonium group, as well sulfonium or an arsonium group. ii) A steroid-like structure inhibitor also important. And iii) free 3 beta-hydroxy group bent conformation cycloartenol, which essential features substrate for methylation reaction, no longer required observe inhibition. data obtained strongly support idea that heteroatoms (N, As, S), substituted triterpenoid derivatives 25, carbocationic high-energy intermediate involved during reaction catalyzed AdoMet-cycloartenol-C-24-methyltransferase.