Synthesis and binding to tubulin of colchicine spin probes

Spin probes of deacetylcholchicine (1), 4-(hydroxymethyl)colchicine (2), and colchifoline (3) have been synthesized to study the binding site for colchicine on tubulin. Acylation of 1-3 with (+/-)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy-3-carboxylic acid (4) afforded diastereomeric mixtures of the est...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1984-12, Vol.27 (12), p.1729-1733
Main Authors: Sharma, Padam N, Brossi, Arnold, Silverton, J. V, Chignell, Colin F
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Brain - metabolism
Chemistry
Colchicine - analogs & derivatives
Colchicine - chemical synthesis
Colchicine - metabolism
Colchicine - pharmacology
Electron Spin Resonance Spectroscopy
Exact sciences and technology
Free radicals chemistry
Indicators and Reagents
Mass Spectrometry
Microtubules - metabolism
Organic chemistry
Protein Binding
Rats
Reactivity and mechanisms
Spin Labels - chemical synthesis
Stereoisomerism
Structure-Activity Relationship
Tubulin - metabolism
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Summary:Spin probes of deacetylcholchicine (1), 4-(hydroxymethyl)colchicine (2), and colchifoline (3) have been synthesized to study the binding site for colchicine on tubulin. Acylation of 1-3 with (+/-)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy-3-carboxylic acid (4) afforded diastereomeric mixtures of the esters 5-8 and the amides 9 and 10. Pure diastereomers of 3 were synthesized with 4a and 4b, which inhibited the binding of colchicine by 60%. In the presence of calf brain microtubular protein, the colchifoline spin labels underwent reduction of the nitroxide group, which precluded their use to study the topography of the colchicine binding site.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00378a035