title: Inhibition of protein synthesis by didemnins: cell potency and SAR.
abstract: Synthetic and naturally occurring didemnins are potent and specific inhibitors of protein synthesis in vitro. Structure-activity analysis indicates a requirement for the intact macrocycle; however, the smaller ring size represented by the didemnin analogue, tamandarin A, is equipotent to didemnin B. Replacement of the N,O-dimethyltyrosine by a N-methylphenylalanine or N-methylleucine residue is also well-tolerated. The rank order for inhibition of 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.
authors.affiliation: Willard H. Dow Laboratory, Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ahuja
authors.forename: A
authors.initials: A
authors.lastname: Geiger
authors.forename: J M
authors.initials: JM
authors.lastname: Ramanjulu
authors.forename: M D
authors.initials: MD
authors.lastname: Vera
authors.forename: B
authors.initials: B
authors.lastname: SirDeshpande
authors.forename: A
authors.initials: A
authors.lastname: Pfizenmayer
authors.forename: M
authors.initials: M
authors.lastname: Abazeed
authors.forename: D J
authors.initials: DJ
authors.lastname: Krosky
authors.forename: D
authors.initials: D
authors.lastname: Beidler
authors.forename: M M
authors.initials: MM
authors.lastname: Joullié
authors.forename: P L
authors.initials: PL
authors.lastname: Toogood
mesh_terms: D000818:Animals; D002474:Cell-Free System; D047630:Depsipeptides; D006801:Humans; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D047630:Depsipeptides; D020648:Peptide Elongation Factor 1; D010456:Peptides, Cyclic; D011500:Protein Synthesis Inhibitors; C030051:didemnins