Flavonoids as colchicine binding site inhibitors: emerging scaffolds in anticancer drug design

Tubulin inhibition remains a well-established strategy in anticancer therapy, mediated primarily through three binding sites on the α-β tubulin heterodimers: taxane, vinca, and colchicine binding site (CBS). Although several clinically approved drugs target the taxane and vinca sites, their efficacy is often compromised by multidrug resistance. In contrast, CBS remains an underexploited yet highly promising target, as no anticancer drug has been approved that specifically binds this site. Flavonoids, a diverse class of naturally occurring polyphenols, share structural features with colchicine and have emerged as potential CBS inhibitors with favourite safety profiles. Reported tubulin-inhibiting flavonoids encompass polymethoxylated (PMF), polyhydroxylated (PHF), and synthetic or semi-synthetic derivatives, with the most potent compounds exhibiting sub micromolar IC50 values. PMFs generally display stronger activity than PHFs, likely due to enhanced lipophilic interactions within the CBS pocket. Synthetic modifications extending beyond the traditional methoxy and hydroxy substituents have further improved potency. Computational modelling and X-ray crystallographic analyses consistently reveal that flavonoids and colchicine share a similar binding orientation at the CBS supporting their potential as scaffolds for rational anticancer drug design. This review highlights the biochemical, structural, and mechanistic features of flavonoids targeting CBS and discusses their promise as leads for novel CBS inhibitors.