ANALOGS OF AMANIN - SYNTHESIS OF ILE3-AMANINAMIDE AND ITS DIASTEREOISOMERIC (S)-SULFOXIDE

Abstract

Ile3-amaninamide (3-R) and its diastereomeric sulfoxide (3-S) were obtained by oxidation of the bicyclic thioether peptide 2 by H2O2 in acetic acid. The peptide 2 was prepared by an intramolecular Savige-Fontana reaction of the linear octapeptide tert-butylester 4 whose N-terminal Boc-Hpi residue on treatment with TFA [trifluoroacetic acid] lost the Boc group and reacted under thioether formation with the released Cys-SH. The concomitantly deprotected carboxyl terminus was coupled intramolecularly with the free amino group of the secocompound 5 using the MA [mixed anhydride] or DCCI [dicyclohexylcarbodiimide] method, forming the homodetic peptide ring. Compounds 3-R and 3-S agreed well with analog samples in chiroptical behavior. Thioether 2 and sulfoxide 3-R exerted 50% inhibition of RNA polymerase 2 (or B) from Drosophila melanogaster in 10-6 M solution; Ki of 3-S was .apprx. 5 times higher.