The effect of the chemical nature of the side chains of amatoxins in the inhibition of eukaryotic RNA polymerase B.
The inhibition constants (Ki) of DNA-dependent RNA polymerase B (or II) from calf thymus were measured for eight synthetically obtained bicyclic amanitin-like thioethers, two R-sulfoxides, and two S-sulfoxides. These Ki values were compared with those of alpha-amanitin, its 6'-O-methylether Ia (an R-sulfoxide), the S-sulfoxide, the sulfone, the S-deoxo derivative (Id) of Ia, and several previously described amatoxins. The necessity of a beta-methyl side chain in position 3 and a hydroxy group in proline-2 was confirmed. Additionally, the presence of an isoleucine side chain in position 6 and the absence of a side chain in position 5 was recognized as important for binding to the enzyme. In the three sulfoxide samples examined, the R-diastereomer was found to be a stronger inhibitor than the S-form. The contribution of every structural element to biological activity has been discussed.
D000546:Amanitins / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D051379:Mice; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology*
D000546:Amanitins; C018207:amatoxin; D012319:RNA Polymerase II; D012321:DNA-Directed RNA Polymerases