Structure-Activity Analysis of the Interaction of Curacin A, the Potent Colchicine Site Antimitotic Agent, with Tubulin and Effects of Analogs on the Growth of MCF-7 Breast Cancer Cells
- Pascal Verdier-Pinard1,
- Jing-Yu Lai2,
- Hae-Dong Yoo3,
- Jurong Yu2,
- Brian Marquez3,
- Dale G. Nagle3,
- Mitch Nambu4,
- James D. White4,
- J. R. Falck2,
- William H. Gerwick3,
- Billy W. Day5 and
- Ernest Hamel1
- 1Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment, and Diagnosis, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702 (P.V.-P., E.H.), Departments of 2Biochemistry and Pharmacology, Southwestern Medical Center, The University of Texas at Dallas, Dallas, Texas 75235 (J.Y.L., J.Y., J.R.F.), 3College of Pharmacy, Oregon State University, Corvallis, Oregon 97331 (H.-D.Y., B.M., D.G.N., W.H.G.), 4Department of Chemistry, Oregon State University, Corvallis, Oregon 97331 (M.N., J.D.W.), and Departments of 5Environmental and Occupational Health and of Pharmaceutical Sciences, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15238 (B.W.D.)
Abstract
Originally purified as a major lipid component of a strain of the cyanobacterium Lyngbya majuscula isolated in Curaçao, curacin A is a potent inhibitor of cell growth and mitosis, binding rapidly and tightly at the colchicine site of tubulin. Because its molecular structure differs so greatly from that of colchicine and other colchicine site inhibitors, we prepared a series of curacin A analogs to determine the important structural features of the molecule. These modifications include reduction andE-to-Z transitions of the olefinic bonds in the 14-carbon side chain of the molecule; disruption of and configurational changes in the cyclopropyl moiety; disruption, oxidation, and configurational reversal in the thiazoline moiety; configurational reversal and substituent modifications at C13; and demethylation at C10. Inhibitory effects on tubulin assembly, the binding of colchicine to tubulin, and the growth of MCF-7 human breast carcinoma cells were examined. The most important portions of curacin A required for its interaction with tubulin seem to be the thiazoline ring and the side chain at least through C4, the portion of the side chain including the C9–10 olefinic bond, and the C10 methyl group. Only two modifications totally eliminated the tubulin-drug interaction. The inactive compounds were a segment containing most of the side chain, including its two substituents, and analogs in which the methyl group at the C13 oxygen atom was replaced by a benzoate residue. Antiproliferative activity comparable with that observed with curacin A was only reproduced in compounds that were potent inhibitors of the binding of colchicine to tubulin. Molecular modeling and quantitative structure-activity relationship studies demonstrated that most active analogs overlapped extensively with curacin A but failed to provide an explanation for the apparent structural analogy between curacin A and colchicine.
Footnotes
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Send reprint requests to: Dr. E. Hamel, Building 37, Room 5D02, NIH, Bethesda, MD 20892-4255.
- Abbreviations:
- HPLC
- high performance liquid chromatography
- GC
- gas chromatography
- EIMS
- electron ionization mass spectrometry
- QSAR
- quantitative structure-activity relationship(s) CHARMm, chemistry at Harvard macromolecular mechanics
- MOPAC
- molecular orbital package
- CNDO
- complete neglect of differential overlap
- MNDO
- modified neglect of differential overlap
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- Received March 26, 1997.
- Accepted September 15, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
