Synthesis and biological activity of chimeric structures derived from the cytotoxic natural compounds dolastatin 10 and dolastatin 15

Journal of Medicinal Chemistry
J PoncetP Jouin

Abstract

The natural cytotoxic compounds dolastatins 10 and 15 exhibit great similarities in structure and in their biological activity profiles. Two compounds (1 and 2) formed by interchanging the dolaisoleuine residue of dolastatin 10 and the MeVal-Pro dipeptide of dolastatin 15 were synthesized in order to evaluate the possible equivalence of these units. These compounds can be considered as chimeras of dolastatins 10 and 15 formed by the N-terminal part of the former and the C-terminal part of the latter and vice versa. Both analogues exhibited a marked decrease in their cytotoxic activity but showed similar differential cytotoxicity with regard to the cell lines assayed compared with the parent compounds. HT-29 cell line was the least sensitive one. However, this activity was in the nanomolar level and close to that of vincristine. The differences in their effect on tubulin polymerization were less pronounced. We confirmed the already known crucial role of the Dil residue in this assay. The nonequivalence of the Dil unit and the MeVal-Pro dipeptide probably reflects modification in the relative positions of the N-dimethylamino and the phenyl moieties.

References

Mar 1, 1973·Proceedings of the National Academy of Sciences of the United States of America·M L ShelanskiC R Cantor
Mar 17, 1993·Journal of the National Cancer Institute·M BeckwithD L Longo
Oct 1, 1995·Chemical & Pharmaceutical Bulletin·K MiyazakiS Tsukagoshi
Oct 1, 1995·Journal of Computer-aided Molecular Design·P FantucciA M Villa

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Citations

Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·J PoncetP Jouin
Jan 31, 2008·Journal of the American Chemical Society·Pixu LiMadeleine M Joullié
Dec 15, 2005·Journal of the American Chemical Society·Arie ZaskFrank Loganzo

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