SYNTHESIS AND BIOLOGICAL CHARACTERIZATION OF A SERIES OF IBERIOTOXIN ANALOGS

We report here the synthesis of iberiotoxin (IbTX), a 37-amino acid pe ptide containing three disulfide bridges, and a series of mono-looped analogues. All syntheses were conducted using Fmoc chemistry. Synthesi s of IbTX gave a product which was indistinguishable from a reference sample in both its physico-chemical properties and its biological acti vity. A series of three mono-looped analogues, in which four of the si x cysteines were replaced by alanine, were synthesised to give [Ala(7, 13,28,33)]-IbTX, [Ala(13,17,33,35)]-IbTX and [Ala(7,17,28,35)]-IbXT. O xidation of the linear form of [Ala(7,17,28,35)]-IbTX to form the Cys( 13) to Cys(33) disulfide bridge proceeded more slowly than that of the other two analogues. None of these analogues was biologically active, indicating that no single loop is the mediator of channel blocking ac tivity. (C) Munksgaard 1995.