Colchicine analogues

Gradus-Pizlo I, Wilensky RL, March KL, et al. Local delivery of biodegradable microparticles containing colchicine or a colchicine analogue effects on restenosis and implications for catheter-based drug delivery. J Am Coll Cardiol 1995 26(6) 1549-1557. 

Schroder and co-workers studied the addition of formaldehyde-O-oxide, generated in situ at low temperature by ozonolysis of ketene diethylacetal, to the tropolonic ring of various colchicine analogues, Fig. (4) [80]. The intermediate ozonide E formed from 4 decomposed upon warming to give A-acetylcolchinol methyl ether 32 via the presumed intermediate F, in 81% yield. 

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. 

Blokhin, A. V., Yoo, H., Geralds, R. S., Nagle, D. G., Gerwick, W. H., and Hamel, E., Characterization of the interaction of the marine cyanobacterial natural product Curacin A with the colchicine site of tubulin and initial structure-activity studies with analogues, Mol. Pharmcol., 48, 523, 1995. 

HTI-286 binds to the tubulin heterodimer and induces formation of 13-membered tubulin rings [138], Photoaffinity labeling with analogues of HTI-286 mapped to residues of a-tubulin close to the interdimer interface [139], Competitive binding assays with dolastatin-10, cryptophycin A, vinblastine, PTX and colchicines, indicate that the hemiasterlins bind in a subsite of the Vinca domain, which is located at the interdimer interface [28],... 

CoMFA CA4 analogues Hypothesis of a different pharmacophore for combretastatins and the other CSI colchicine, podophyllotoxin and phenstatin [26]... 

After the pioneering work of Rapoport and Cook in the early 1950 s, aimed at elucidating the structure of major colchicine degradation products, there were only a few reported total syntheses of allocolchicines, in part due to their easy availability by semi-synthesis. These syntheses are reviewed below, along with new synthetic approaches giving rise to analogues. 

In the course of their synthesis of colchicine [102], Banwell and coworkers found that the tricyclic intermediate 74, Fig. (15), aromatized in the presence of //-toluenesulfonic acid to give the colchinol analogue 75 [103]. The methyl ester 76 and the previously described methyl ether 72 obtained from 75 were found to be potent inhibitors of tubulin polymerization. 

Compound 30 <2002JME1901>, an improved curacin A analogue, was found to have potent antiproliferative activity in human breast, prostate, and ovarian cancer. It can replace colchicin from tubulin and inhibits the GTP/ glutamate-induced polymerization of tubulin effectively. Pharmaceutical studies suggest that the oxime moiety in compound 30 may serve as a (Z)-alkene bioisostere. 

Some years ago a benzothiophene that exhibited some activity as a tubulin polymerization inhibitor and appeared to bind weakly to the colchicine binding domain of tubulin was reported. This finding stimulated the synthesis of several benzofuran and indole analogues, Fig. (17). 

Benzo[b]furan and indole analogues of some recently identified benzo[b]thiophene inhibitors of tubulin polymerization have been synthesized, and their biological activity has been investigated. Among them, the compound 2-(3-hydroxy,4-methoxyphenyl),3-(3,4,5-trimethoxybenzoyl)-6-methoxyfuran-2-one 81 was the most active, exhibiting 5 times the level of potency of Combretastatin A-4. However, it is less potent than Combretastatin A-4 as inhibitor of [3H]colchicine... 

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