RESUMO
α-Quaternary α-ethynyl α-amino acids are an important class of non-proteinogenic amino acids that play an important role in the development of peptides and peptidomimetics as therapeutic agents and in the inhibition of enzyme activities. This review provides an overview of the literature concerning synthesis and applications of α-quaternary α-ethynyl α-amino acids covering the period from 1977 to 2015.
Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Peptídeos/química , Peptídeos/síntese químicaRESUMO
This review focuses on a new solid-phase synthetic strategy for an anticancer natural product yaku'amide B (1) and its target identification and structure-function relationship study using synthetic analogues and probes. To realize the Fmoc-based solid-phase synthesis of 1, we developed new synthetic methods for enamide formation. Namely, modified traceless Staudinger ligation using alkenyl azides and newly designed phosphinophenol esters enabled stereoselective construction of the (E)- and (Z)-ΔIle moieties. Furthermore, resin-cleavage and C-terminus modification were simultaneously achieved with an ester-amide exchange reaction using C-terminal amine and AlMe3, which successfully afforded 1 via a full solid-phase route. The developed strategy was applied to the construction of seven E/Z isomers of 1. In the target identification of 1, fluorescent imaging study and affinity pull-down assay using the synthetic probes revealed that 1 exerts potent cytostatic activity by binding to subunits α and ß of mitochondrial FoF1-ATP synthase. On the basis of the mode of action of 1, we conducted biological evaluation of the seven E/Z-isomers of 1. Assessment of growth inhibition activity and the effect on FoF1-ATP synthase indicates that the E/Z-stereochemistry of the three ΔIle residues controls the magnitude of biological functions of 1.