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 IC 50 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.

Makaleyi görüntüle

Premise Whole-genome duplications (WGDs) are prevalent throughout the evolutionary history of plants. For example, dozens of WGDs have been phylogenetically localized across the order Brassicales, specifically, within the family Brassicaceae. A WGD event has also been identified in the Cleomaceae, the sister family to Brassicaceae, yet its placement, as well as that of WGDs in other families in the order, remains unclear. Methods Phylo-transcriptomic data were generated and used to infer a nuclear phylogeny for 74 Brassicales taxa. Genome survey sequencing was also performed on 66 of those taxa to infer a chloroplast phylogeny. These phylogenies were used to assess and confirm relationships among the major families of the Brassicales and within Brassicaceae. Multiple WGD inference methods were then used to assess the placement of WGDs on the nuclear phylogeny. Results Well-supported chloroplast and nuclear phylogenies for the Brassicales and the putative placement of the Cleomaceae-specific WGD event Th-ɑ are presented. This work also provides evidence for previously hypothesized WGDs, including a well-supported event shared by at least two members of the Resedaceae family, and a possible event within the Capparaceae. Conclusions Phylogenetics and the placement of WGDs within highly polyploid lineages continues to be a major challenge. This study adds to the conversation on WGD inference difficulties by demonstrating that sampling is especially important for WGD identification and phylogenetic placement. Given its economic importance and genomic resources, the Brassicales continues to be an ideal group for assessing WGD inference methods.

Makaleyi görüntüle