Inhibition of protein synthesis by didemnins: Cell potency and SAR

Synthetic and naturally occurring didemnins are potent and specific inhibit ors of protein synthesis in vitro. Structure-activity analysis indicates a requirement for the intact macrocycle; however, the smaller ring size repre sented by the didemnin analogue, tamandarin A, is equipotent to didemnin B. Replacement of the N,O-dimethyltyrosine by a N-methylphenylalanine or N-me thylleucine residue is also well-tolerated. The rank order for inhibition o f protein synthesis in vitro appears to be retained in MCF-7 cells, albeit at much higher potency. This increase in potency is explained for the first time by data indicating that MCF-7 cells can accumulate didemnin B up to 2 -3 orders of magnitude compared to the growth medium.