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J. Biol. Chem., Vol. 277, Issue 35, 32165-32171, August 30, 2002

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()-Doliculide, a New Macrocyclic Depsipeptide Enhancer of Actin Assembly^*

Ruoli Bai, David G. Covell, Chunfeng Liu^§, Arun K. Ghosh^§, and Ernest Hamel^¶

From the  Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI National Institutes of Health, Frederick, Maryland 21702 and the ^§ Department of Chemistry, University of Illinois, Chicago, Illinois 60607

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 G₂/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.

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