Abstract by Diego Moya
Chemistry and Biochemistry
Synthesis of Yaku\'amide A Analogues
Yaku’amide A (YA) is a structurally unique peptide, rich in dehydroamino acids and b-hydroxyamino acids. This compound exerts potent growth inhibitory effects against P388 mouse leukemia cell lines (IC50 = 0.88 nM). Recent studies have suggested that YA depletes ATP by inhibiting ATP synthesis and enhancing ATP hydrolysis.The structure of YA presents complex and unsymmetrical bulky dehydroamino acids (DAAs) such as E- and Z- dehydroisoleucine (D-Ile), which pose a synthetic challenge. Despite work by the Inoue group and a more efficient route developed in our lab, synthesis remains lengthy. Via computational studies, conducted by former SCCR fellow David Kastner, we have identified two analogues which closely resemble YA’s conformation. The use of simpler and symmetrical bulky DAAs such as dehydrovaline (DVal) and dehydroethylnorvaline (DEnv) will substitute for DIle in positions , , and . The objective is to synthesize the two candidate structures and submit them for biological testing. Our hypothesis is that at least one of them will retain the inhibitory effects of YA.