Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

Abstract

It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

“…The pyridyl ring is positioned deep in the colchicine binding site, away from the a/b interface, and is stabilised through hydrophobic interactions with residues in the b subunit. Since all these compounds have good binding energies, yet lack activity, it could be postulated that a polar interaction with bCys241, or at least the positioning of possible polar interaction partners in the proximity of this residue is crucial for the observed anticancer activity, as has been seen for other colchicine binding site inhibitors [44][45][46] . However, an exception can be seen at compound 11k, which showed selective activity against nine cancer cell lines (GI > 70%), and also inhibited tubulin polymerisation in vitro, but did not form a favourable contact with this residue in our docking experiments.…”

Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells

“…Colchicine-tubulin binding is a slow, strongly temperature-dependent, and practically irreversible process [173]. Although colchicine has been used clinically in the treatment of nonneoplastic diseases (gout, familial Mediterranean fever), neither colchicine nor other related compounds were successful as chemotherapeutic agents owing to their severe toxicity to normal tissues at doses required for antitumor effects [174,175]. The experimental evidence indicates that the inhibitory effect of maytansine-site ligands is a direct consequence of the occupation of the β-tubulin pocket.…”

“…Colchicine-tubulin binding is a slow, strongly temperature-dependent, and practically irreversible process [173]. Although colchicine has been used clinically in the treatment of nonneoplastic diseases (gout, familial Mediterranean fever), neither colchicine nor other related compounds were successful as chemotherapeutic agents owing to their severe toxicity to normal tissues at doses required for antitumor effects [174,175]. Over the last few decades, compounds of low toxicity which target the colchicine site have been reported (Figure 7), including derivatives of stilbenoid-combretastatins (combretastatin A-1 phosphate/OXi4503, combretastatin A-1, combretastatin A-4, fosbretabulin, ombrabulin), chalcones (MDL 27048), compounds with furonaphthodioxole skeleton (podophyllotoxin), derivatives of indole (indibulin), and natural metabolite of estradiol (2-methoxyestradiol).…”

Conventional and microwave reactions of 1,3‐diaryl‐5,4‐enaminonitrile‐pyrazole derivative with expected antimicrobial and anticancer activities

“…Pyrazole derivatives have a broad spectrum of biological activities such as antiviral, antagonist, antimicrobial, antibacterial, anticancer, anti‐inflammatory, analgesic, anthelmintic, herbicidal, acaricidal and insecticidal, antimitotic, and antioxidant activities …”