Divergent Solid‐Phase Synthesis and Biological Evaluation of Yaku'amide B and Its Seven <i>E</i>/<i>Z</i> Isomers
Koichi Kamiya, Kensuke Miura, Hiroaki Itoh, Masayuki Inoue
Abstract
-ATP synthase, inhibits ATP production, and enhances ATP hydrolysis. The presence of one (E)- and two (Z)-α,β-dehydroisoleucines (ΔIle) in the linear 13-mer sequence is the most unusual structural feature of 1. To uncover the biological importance of these residues, we synthesized 1 and its seven E/Z isomers 2-8 by devising a new divergent solid-phase strategy. Both the (E)- and (Z)-ΔIle residues were stereoselectively constructed by traceless Staudinger ligation on resin to ultimately deliver 1-8. All isomers 2-8 displayed effects on the inhibition of cell growth and ATP production, and enhanced ATP hydrolysis, thus indicating that 2-8 share the same mode of action as 1. The least potent isomer, 8, was isomeric at three ΔIle residues of the most potent 1. These findings together indicate that the E/Z stereochemistry of the three ΔIle residues controls the magnitude of the biological functions of 1.