(-)-Doliculide, a new macrocyclic depsipeptide enhancer of actin assembly.
The cytotoxic, cyclic depsipeptide (-)-doliculide was originally isolated by Ishiwata et al. (Ishiwata, H., Nemoto, T., Ojika, M., and Yamada, K. (1994) J. Org. Chem. 59, 4710-4711 and Ishiwata, H., Sone, H., Kigoshi, H., and Yamada, K. (1994) J. Org. Chem. 59, 4712-4713) from the sea hare Dolabella auricularia collected in Japanese waters, but the mechanism of action of the depsipeptide was not known. Using synthetic (-)-doliculide, we found that the compound arrests cells at the G(2)/M phase of the cell cycle by interfering with normal actin assembly. In cells, normal stress fibers disappeared and were replaced by multiple clumps of apparently aggregated F-actin. These effects of (-)-doliculide on cells were essentially identical to those obtained with jasplakinolide. Like jasplakinolide, (-)-doliculide caused the hyperassembly of purified actin into F-actin as measured both fluorometrically and by centrifugation. In addition, (-)-doliculide, like jasplakinolide, readily displaced a fluorescent phalloidin derivative from actin polymer. In these biochemical assays (-)-doliculide and jasplakinolide were quantitatively virtually identical in their behaviors. Similar effects have also been reported with a series of depsipeptides known as chondramides. Using recently developed, computer-driven shape descriptor analysis (Mansfield, M. L., Covell, D. G., and Jernigan, R. L. (2002) J. Chem. Inf. Comput. Sci. 42, 259-273), we compared (-)-doliculide with jasplakinolide, phalloidin, and chondramide C to gain insight into a possible pharmacophore that would explain the apparent binding of this diverse group of molecules at the same site on F-actin. We found that the segment of (-)-doliculide that best overlapped the other molecules encompassed its phenyl and isopropyl side chains and the portion of the macrocycle between these substituents.
Bai
Ruoli
R
Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Covell
David G
DG
Liu
Chunfeng
C
Ghosh
Arun K
AK
Hamel
Ernest
E
D000199:Actins / Q000096:biosynthesis*; D000818:Animals; D002051:Burkitt Lymphoma; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure*; D047630:Depsipeptides; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D008974:Mollusca; D018482:Muscle, Skeletal / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011817:Rabbits; D014407:Tumor Cells, Cultured
D000199:Actins; D047630:Depsipeptides; D010456:Peptides, Cyclic; C424144:doliculide; C057531:jasplakinolide