Tubulin colchicine binding site

The 14C-chloroacetate of 7V-acetylcolchinol 199 and the 14C-isothiocyanate 200 were also found to react covalently with tubulin, but in a non-specific manner167, contrary to compounds 197 and 198 which react covalently with the colchicine binding site on tubulin with a -subunit a-subunit marking ratio169 of about 4 1. 

Colchicine (6) was isolated by Pelletier and Caventou in 1820 and is the main alkaloid of the poisonous meadow saffron plant (Colchicum autum-nale L.) [12-16]. Following some considerable debate over colchicine s structure [17-20] and its successful synthesis [21-26], colchicine was found to bind to tubulin at what is referred to as the colchicine binding site [1,27]. 

Combretastatins are a class of compounds originally derived from the African Willow tree (Combretum caffrum) and are powerful reversible inhibitors of tubulin polymerization. This class of molecules has been shown to bind to the colchicine binding site of tubulin, by the same mode of action as mentioned above (Sect. 1.2). Combretastatins consist of a ris-slilbcnc core structure. To date, there have been several compounds that have shown promise as potential anticancer drugs. However, development of these compounds as anticancer agents is limited by issues of chemical stability, bioavailibilty, toxicity, and solubility. 

Cortese F, BhattacharyyaB, Wolff J, Podophyllo toxin as a probe for the colchicine binding site of tubulin, /5zh/ Chem 252 1134—1140, 1977. 

In looking at these conclusions, one could speculate that rings A and C in these spindle toxins are most important, and they may bind to different loci on the colchicine binding site. It is suspected that two sites of tubulin which respectively bind to rings A and C of colchicine and its bioactive analogs are part of a polypeptide segment which is arranged in a helix, as shown in Fig. 28. 

The colchicine binding site in tubulin was initially identified using a colchicine derivative bearing a sulfhydryl group, permitting unambiguous orientation of the ligand in the electron density map [15]. We have also determined the structure of... 

Fig. 4 Left, location of the vinblastine and colchicine binding sites in tubulin (1Z2B structure), a- and (3-tubulin are represented as yellow and magenta ribbons, respectively vinblastine and DAMA-colchicine are represented as green and cyan spheres, respectively GTP and GDP are represented as pink sticks. Vinblastine binds at the interdimer interface, whereas colchicine binds at the intradimer interface. Right, zoom on the vinblastine binding site. Secondary structure elements contacting vinblastine are colored blue...

Colchicine itself and colchicine analogues predominantly bind to a high affinity site, the so-called colchicine binding site located at the intradimer interface between a- and P-tubulin, facing the lumen of the microtubule. Colchicine (1) Fig. (1) inhibits microtubule formation and disrupts microtubules as a tubulin destabilising agent. 

A second group of tubulin inhibitors is represented by compounds exhibiting the combretastatin structure. Combretastatin (5) itself, as well as combretastatins A-l (5a), A-4 (5b) and A-2 (5d), have first been extracted from a South African tree Combretum caffrum by Pettit et al., depicting affinity to the colchicine binding site [28], Syntheses of various analogues of this simple molecule, thereafter, have been reported [16,29, 30] (see also Scheme 1). 

SAR information about a series of 3-aminobenzophenone compounds (e.g. 6d and 6e), based on the mimic of the aminocombretastatin molecular skeleton, revealed that by the introduction of an amino group instead of a hydroxy group inhibition of tubulin polymerisation through binding to the colchicine binding site could fully be preserved or even improved [42]. 

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