title: Structure--activity relationships of the didemnins.
abstract: 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.
authors.affiliation: Roger Adams Laboratory, University of Illinois, Urbana 61801, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sakai
authors.forename: K L
authors.initials: KL
authors.lastname: Rinehart
authors.forename: V
authors.initials: V
authors.lastname: Kishore
authors.forename: B
authors.initials: B
authors.lastname: Kundu
authors.forename: G
authors.initials: G
authors.lastname: Faircloth
authors.forename: J B
authors.initials: JB
authors.lastname: Gloer
authors.forename: J R
authors.initials: JR
authors.lastname: Carney
authors.forename: M
authors.initials: M
authors.lastname: Namikoshi
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.forename: R G
authors.initials: RG
authors.lastname: Hughes
authors.forename: D
authors.initials: D
authors.lastname: García Grávalos
authors.forename: T G
authors.initials: TG
authors.lastname: de Quesada
authors.forename: G R
authors.initials: GR
authors.lastname: Wilson
authors.forename: R M
authors.initials: RM
authors.lastname: Heid
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D047630:Depsipeptides; D004798:Enzymes / Q000187:drug effects; D005260:Female; D019073:HT29 Cells; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014561:Urochordata / Q000737:chemistry; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D047630:Depsipeptides; D004798:Enzymes; D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; D011506:Proteins; C030051:didemnins; D012313:RNA; D004247:DNA