Inhibition of protein synthesis by didemnins: cell potency and SAR.
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.
Ahuja
D
D
Willard H. Dow Laboratory, Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Geiger
A
A
Ramanjulu
J M
JM
Vera
M D
MD
SirDeshpande
B
B
Pfizenmayer
A
A
Abazeed
M
M
Krosky
D J
DJ
Beidler
D
D
Joullié
M M
MM
Toogood
P L
PL
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
D047630:Depsipeptides; D020648:Peptide Elongation Factor 1; D010456:Peptides, Cyclic; D011500:Protein Synthesis Inhibitors; C030051:didemnins