Colchicine and its analogues: Recent findings

The importance of the phenyl‐tropolone ‘aS’ configuration in colchicine's binding to tubulin

“…Titration of tubulin with deacetamidocolchicine gave CD spectra similar to those observed with (_)-colchicine ( fig.2D), confirming that it is indeed the aS conformer of deacetamidocolchicine which binds to tubulin, leaving the aR conformer unbound, and thus resulting in a positive CD band. Unlike ( + )-colchicine, the net positive CD band of the unbound deacetamidocolchicine observed in the presence of tubulin was gradually reduced and finally disappeared after about 24 h. This agreed with our expectations since reestablishment of an aS-aR equilibrium from a predominantly aR conformer to equal concentrations of aS and aR conformers (which give no CD band), takes place at the rate of the biaryl isomerization, which has been reported to be in the range of 1 x 10 -4 s -~ for a number of colchicinoids [6,14]. Although reduction of optical rotation of natural (-)-colchicine on binding to tubulin was previously reported [17], the present study with (+)-colchicine and (+)-deacetamidocolchicine provides the first demonstration that it is the ( -)-(aS) enantiomer which binds to the protein, leaving the (+)-(aR) enantiomer unbound.…”

“…Support for this conclusion is based on the following: In addition to atomic chirality at C-7, colchicine also possess axial chirality originating from the phenyl-tropolonic moiety. A recent NMR study [6] revealed that colchicinoids can undergo aS-aR phenyl-tropolonic isomerization [6,14] and the position of the aS-aR equilibria appears to be dependent upon the nature of the substituents at C-7 of ring B [6]. NMR spectral analysis indicated that both (C)-7 acetamido groups of natural (7S)-and unnatural (7R)-colchicine prefer the equatorial over the axial orientation.…”

“…Although the results of antitumor activity and tubulin binding studies of a large number of cholchicinoids had indicated the importance of the spatial arrangement of the four methoxy groups in the drug-protein interaction, the mechanism of interaction is still not clearly understood. A recent report [6] Note: The italic letter a before the corresponding R and S denotes an axial chirality originating from a biaryl system as suggested by Calm et al [1] with the protein would therefore deserve special attention. Support for this hypothesis has now been …”

Colchiceine Complexes with Lithium, Sodium and Potassium Salts − Spectroscopic Studies

“…It shows antimitotic, antifibrotic and anti-inflammatory activity [1] and can efficiently alleviate the symptoms of gout attack when applied in the early phase. More recently, it has been introduced in the treatment of Mediterranean fever.…”

Drug–tubulin interactions interrogated by transient absorption spectroscopy

“…11 It is an important bioactive drug as well as a neurotoxin in animal models of Alzheimer's disease and epilepsy. [12][13][14] Although COL has been shown to possess antitumor properties, 15,16 its therapeutic use is limited by toxicity problems; this has led to the consideration of analogs. [17][18][19] When COL binds to TU, it inhibits the assembly into microtubules and microtubule dynamics.…”