Synthesis of macrocycles that inhibit protein synthesis: stereochemistry and structural based studies on sanguinamide B derivatives

We report the synthesis of seven new sanguinamide B (SanB) analogues. Substitution of amino acids along the backbone of SanB and testing in HCT-116 colon cancer cell lines identified new biologically active SanB derivatives. These compounds establish a structure–activity relationship and show that a Cbz-lysine moiety is important for biological activity. We also identified the most effective stereochemistry at each position around the molecule. The biological activity of the macrocycle is extremely sensitive to stereochemistry and amino acid placement.