Generation and Biological Evaluation of Degraded Derivatives of the Three E/Z-Isomers of Yaku’amide B

Abstract

Potently cytostatic yaku’amide B (1) is a highly unsaturated linear tridecapeptide. During our synthetic studies of the E/Z-isomers of the α,β-dehydroisoleucines of 1, an unexpected retro-aldol reaction proceeded to transform E/Z-isomers 2, 3, and 4 into 2a, 3a, and 4a/4b, respectively. Compounds 2a, 3a, and 4a have a glycine at residue-1 instead of β-hydroxyisoleucine, and the β-hydroxyvaline at residue-8 in 4a is further replaced by glycine in 4b. Evaluation of the growth inhibition activities against MCF-7 cells revealed that 4b was approximately 10-fold weaker than the equipotent 2–4 and 2a–4a, demonstrating the biological importance of a bulky side chain at residue-8.

Synthesis and evaluation of potent yaku'amide A analogs

“…Inoue and co-workers recently observed slow retro-aldol reactions of unnatural E / Z isomers of yaku'amides upon storage in the presence of dilute acetic acid. 20 This cleavage occurs at the β-OH residues that are adjacent to the ΔAAs and is presumably the result of increased steric hindrance ( i.e. , A 1,3 strain) caused by the unnatural alkene isomers.…”