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Molecular Pharmacology, Vol 13, 232-241, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Tubulin Binding Affinities of Podophyllotoxin and Colchicine Analogues

JOANNE K. KELLEHER 1

1 Department of Biology, Boston University, Boston, Massachusetts 02215

The lignan podophyllotoxin competitively inhibits colchicine binding to tubulin. The ability of 12 podophyllotoxin and three colchicine analogues to inhibit colchicine binding to mouse brain tubulin was investigated in order to identify drugs with high affinity for the colchicine binding site on tubulin. Colchicine binding was assayed by the DEAE-cellulose filter paper method. Results indicated that podophyllotoxin binds to tubulin more rapidly and in less temperature-dependent fashion than colchicine. All active drug analogues were competitive inhibitors. beta-Peltatin was found to have a significantly greater affinity for mouse brain tubulin than either podophyllotoxin or colchicine. Analogues containing hydrophilic substitutions had greatly reduced tubulin binding activity, as did stereoisomers of podophyllotoxin. Other results suggest that the conformation about the lactone ring on podophyllotoxin may be of importance in determining tubulin binding activity. These results are consistent with the hypothesis that the colchicine binding site is located in a hydrophobic pocket. Tubulin binding assays in vitro are suggested as useful steps in the screening of antitumor agents.

Note:
ACKNOWLEDGMENTS The author wishes to thank Drs. L. Margulis, T. N. Margulis, W. J. Gensler, I. D. Raacke, and S. Mohr for advice and suggestions.

Submitted on August 4, 1976
Accepted on October 19, 1976




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Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics