Regioselective approach to colchiceine tropolone ring functionalization at C(9) and C(10) yielding new anticancer hybrid derivatives containing heterocyclic structural motifs

Abstract

The influence of base type, temperature, and solvent on regioselective C(9)/C(10) “click” modifications within the tropolone ring of colchiceine (2) is investigated. New ether derivatives of 2, bearing alkyne, azide, vinyl, or halide aryl groups enable assembly of the alkaloid part with heterocycles or important biomolecules such as saccharides, geldanamycin or AZT into hybrid scaffolds by dipolar cycloaddition (CuAAC) or Heck reaction. Compared to colchicine (1) or colchiceine (2), ether congeners, as e.g. 3e [IC₅₀s_(3e) ∼ 0.9 nM], show improved or similar anticancer effects, whereby the bulkiness of the substituents and the substitution pattern of the tropolone proved to be essential. Biological studies reveal that expanding the ether arms by terminal basic heterocycles as quinoline or pyridine, decreases the toxicity in HDF cells at high anticancer potency (IC₅₀s ∼ 1–2 nM). Docking of ether and hybrid derivatives into the colchicine pocket of α_GTP/β tubulin dimers reveals a relationship between the favourable binding mode and the attractive anticancer potency.

Graphical Abstract

Keywords:

• Colchiceine tautomers
• click
• heck reaction
• tubulin inhibitors
• anticancer

Acknowledgement

The authors wish to thank dr. Joanna Kurek for obtaining and purification of colchiceine samples.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Polish National Science Centre (NCN) under Grant Opus 13 no. UMO-2017/25/B/ST5/00291.