Divergent Solid‐Phase Synthesis and Biological Evaluation of Yaku'amide B and Its Seven E/Z Isomers

Abstract

Yaku′amide B (1) inhibits cancer cell growth through a unique mechanism of action. Compound 1 binds to mitochondrial FoF1‐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.

Recent Progress in Solid‐Phase Total Synthesis of Naturally Occurring Small Peptides

“…In this manner, bogorol A was successfully obtained by acid-mediated cleavage from the resin. Similarly, the combination of Staudinger ligation and solid-phase synthesis provides an efficient way to yield yaku'amide B (31) [41,42] and nobilamides B (32) [43,44] and the cyclic depsipeptide nobilamide D. [43] The aromatic δ-amino acids, like p-aminobenzoic acid, and its analogues are unique building blocks contained in the natural linear peptides, such as cystobactamids, [45][46][47][48] albicidin [49,50] and coralmycin A (38). [51] Due to the low reactivity of aromatic amines in the coupling with carboxylic acids, incorporation of the aromatic δ-amino acids into the peptide chain remains challenging.…”

“…In this manner, bogorol A was successfully obtained by acid‐mediated cleavage from the resin. Similarly, the combination of Staudinger ligation and solid‐phase synthesis provides an efficient way to yield yaku'amide B ( 31 ) [41,42] and nobilamides B ( 32 ) [43,44] and the cyclic depsipeptide nobilamide D [43] …”

Convergent Total Synthesis of Yaku'amide A

“…For example, the requirement for large excesses of precious intermediates that are challenging to construct attenuates the benefit offered by the high overall yield. [26] Perhaps more significant is the fact that solid-phase peptide synthesis requires a linear rather than convergent synthetic strategy. Our route complements Inoues work by avoiding excess amounts of valuable subunits and by proceeding in a convergent fashion.…”

“…Although Inoue's solid‐phase synthesis of 2 possesses some advantages such as a higher yield (9.1 %) and fewer required purifications, [5c] it also has some intrinsic limitations. For example, the requirement for large excesses of precious intermediates that are challenging to construct attenuates the benefit offered by the high overall yield [26] . Perhaps more significant is the fact that solid‐phase peptide synthesis requires a linear rather than convergent synthetic strategy.…”

Synthesis and evaluation of potent yaku'amide A analogs

“…2 c Recently, they have devised a solid-phase synthesis of 1b (ref. 3a ) and demonstrated that the E / Z stereochemistry of the ΔIle residues modulates its anticancer activity. 3 b…”