Inhibition of Protein Synthesis by Didemnins:  Cell Potency and SAR

• Published in: Journal of medicinal chemistry 2000-11, Vol.43 (22), p.4212-4218
• Main Authors: Ahuja, Deepika, Geiger, Adam, Ramanjulu, Joshi M, Vera, Matthew D, SirDeshpande, Bhagyashri, Pfizenmayer, Amy, Abazeed, Mohamed, Krosky, Daniel J, Beidler, David, Joullié, Madeleine M, Toogood, Peter L
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell-Free System; Depsipeptides; Humans; Medical sciences; Miscellaneous; Peptide Elongation Factor 1 - antagonists & inhibitors; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Protein Synthesis Inhibitors - chemistry; Protein Synthesis Inhibitors - pharmacology; Rabbits; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000168v

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.