Chloroacetates of 2- and 3-demethylthiocolchicine: Specific covalent interactions with tubulin with preferential labeling of the β-subunit

Add time:07/14/2019    Source:sciencedirect.com

We synthesized two chemically reactive A ring modified analogs of colchicine, 2-chloroacetyl-2-demethylthiocolchicine (2-CTC) and 3-chloroacetyl-3-demethylthiocolchicine (3-CTC). Both are similar to colchicine as inhibitors of tubulin polymerization and act as competitive inhibitors of colchicine binding (apparent Ki values, 3 μM). [14C]-labeled 2-CTC and 3-CTC bound to tubulin at 37°C but not at 0°C, and bound drug formed covalent bond(s) with tubulin. The binding and covalent reactions were inhibited by podophyllotoxin. About 60% of the bound 3-CTC rapidly formed a covalent bond with tubulin. With 2-CTC the covalent reaction was slower than the binding reaction, and only one-third of the bound 2-CTC reacted covalently with tubulin. The ratio of radiolabel in β-tubulin to that in α-tubulin was about 4:1 with both 2-CTC and 3-CTC.

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