dolastatin-11 and Lung-Neoplasms

The synthesis of a lyngbyastatin 1-Ibu-epilyngbyastatin 1 mixture combined with NMR and molecular modeling studies proved that natural lyngbyastatin 1 was only one Ibu epimer rather than a mixture of both and that the configuration of this epimer in the Ibu unit was R. The substance isolated with lyngbyastatin 1 was Ibu-epidolastatin 12. The extreme broadness in the proton NMR spectra of lyngbyastatin 1 and Ibu-epidolastatin 12 was exchange broadening due to rotation about the Ibu-Ala amide bond. It was a consequence of (1) a small energy difference between the cis and trans forms of this bond, (2) a substantial difference in conformation between these forms, and (3) a lowered barrier between them compared to most amide bonds (due to steric hindrance). The synthetic lyngbyastatin 1-Ibu-epilyngbyastatin 1 mixture had significant activities against cancer cells and in stimulating actin polymerization, but was less active than dolastatin 11 in all assays.

Topics: Actins; Antineoplastic Agents; Depsipeptides; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Male; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides; Peptides, Cyclic; Prostatic Neoplasms; Seaweed; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured