Lyngbyastatin 1 and Ibu-epilyngbyastatin 1: synthesis, stereochemistry, and NMR line broadening.
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.
Bai
Ruoli
R
Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick/NIH, Frederick, MD 21702, USA
Bates
Robert B
RB
Hamel
Ernest
E
Moore
Richard E
RE
Nakkiew
Pichaya
P
Pettit
George R
GR
Sufi
Bilal A
BA
D000199:Actins / Q000037:antagonists & inhibitors / Q000187:drug effects; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms; D012624:Seaweed / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000199:Actins; D000970:Antineoplastic Agents; D047630:Depsipeptides; C473053:Ibu-epilyngbyastatin 1; D009842:Oligopeptides; D010456:Peptides, Cyclic; C422265:dolastatin 11; C115557:lyngbyastatin 1