Structure-activity relationships of the didemnins

Ryuichi Sakai, Kenneth L. Rinehart, Vimal Kishore, Bijoy Kundu, Glynn Faircloth, James B. Gloer, John R. Carney, Michio Namikoshi, Furong Sun, Robert G. Hughes, Dolores García Grávalos, Teresa García De Quesada, George R. Wilson, Richard M. Heid

Research output: Contribution to journalArticlepeer-review


Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

Original languageEnglish (US)
Pages (from-to)2819-2834
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number14
StatePublished - Jul 5 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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