Synthesis and cytostatic activities of didemnin derivatives

The highly cytostatic didemnins contain a 23-membered cyclopeptolide with a side chain attached to the backbone through the amine group of threonine. Thirty-six derivatives varying the side chain were prepared, but only compo unds with D-MeLeu attached to threonine show remarkable biological activiti es. To protect the macrocycle from degradation by lipases the two ester bon ds were replaced successively by amide bonds. Although these variations hav e a major effect on the conformation and rigidity of the ring, the compound which contains exclusively amide bonds is highly active, equivalent to ace tyl-didemnin A.