- Structure-activity relationships of the didemnins
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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.
- Sakai, Ryuichi,Rinehart, Kenneth L.,Kishore, Vimal,Kundu, Bijoy,Faircloth, Glynn,Gloer, James B.,Carney, John R.,Namikoshi, Michio,Sun, Furong,Hughes Jr., Robert G.,Grávalos, Dolores García,De Quesada, Teresa García,Wilson, George R.,Heid, Richard M.
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p. 2819 - 2834
(2007/10/03)
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- Pharmaceutical compositions containing didemnins
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This invention is directed to didemnin derivatives, including N-acyl congeners of didemnin A (DA); several DDB-type analogues of DA in which either pyruvic acid has been replaced (with phenylpyruvic acid or alphaketobutyric acid) or proline at position 8 has been replaced [with L-azetidine-2-carboxylic acid (AZT), L-pipecolic acid (Pip), 1-amino-1-carboxylic cyclopentane (acc 5), D-Pro or sarcosine (sar); and other cyclic depsipeptides related to the didemnins, which were isolated from a relatively polar extract of the tunicate T. solidum; namely the didemnins--X [(R)-3-hydroxy-decanoyl-(Gln) 3 -Lac-Pro didemnin A]; Y [(R)-3-hydroxy-decanoyl-(Gln) 4 -Lac-Pro didemnin A]; M (pGlu-Gln-Lac-Pro-didemnin A); N ([Tyr 5 ] didemnin B); nordidemnin N ([Tyr 5 ] nordidemnin B); and epididemnin A ([2S,4R-Hip 2 ] didemnin A).
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