Journal article
Structure−Activity Relationships of the Didemnins
Journal of medicinal chemistry, Vol.39(14), pp.2819-2834
01/01/1996
DOI: 10.1021/jm960048g
PMID: 8709112
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.
Details
- Title: Subtitle
- Structure−Activity Relationships of the Didemnins
- Creators
- Ryuichi Sakai - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainKenneth L Rinehart - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainVimal Kishore - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainBijoy Kundu - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainGlynn Faircloth - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainJames B Gloer - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainJohn R Carney - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainMichio Namikoshi - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainFurong Sun - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainRobert G Hughes - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainDolores García Grávalos - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainTeresa García de Quesada - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainGeorge R Wilson - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), SpainRichard M Heid - Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, Roswell Park Cancer Institute, Buffalo, New York 14263, PharmaMar, U.S.A., Inc., Cambridge, Massachusetts 02139, and PharmaMar, S.A., 28760 Tres Cantos (Madrid), Spain
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.39(14), pp.2819-2834
- DOI
- 10.1021/jm960048g
- PMID
- 8709112
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Language
- English
- Date published
- 01/01/1996
- Academic Unit
- Chemistry
- Record Identifier
- 9984216566402771
Metrics
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