Authors
Karolina Kowalczyk, Andrzej Błauż, Anna Wieczorek-Błauż, Błażej Rychlik, Damian Plażuk
Published in
Dalton transactions (Cambridge, England : 2003). Jul 21, 2026. Epub Jul 21, 2026.
Abstract
Colchicine-site-binding antimicrotubule agents remain promising antimitotic compounds, particularly when structural modification enables retention of tubulin-directed activity while modulating multidrug resistance (MDR) phenotypes. Building on the N-benzyl colchicine scaffold, we synthesised and evaluated a focused series of N-substituted analogues in which the native N-acetyl group was replaced by adamantylmethyl, ferrocenylmethyl or ruthenocenylmethyl, or isomeric o-, m-, and p-ferrocenylbenzyl substituents. The derivatives displayed low-nanomolar antiproliferative activity in drug-sensitive colorectal cancer cell lines, with selected ferrocenylbenzyl analogues and the ruthenocenylmethyl derivative showing particularly high potency. The N-substituent strongly influenced MDR performance: directly attached metallocenylmethyl analogues exhibited pronounced cross-resistance in the ABCG2-overexpressing model, whereas the N-benzyl analogue and selected ferrocenylbenzyl derivatives retained substantial activity and markedly reduced resistance relative to colchicine, especially in the ABCB1-overexpressing model. Cell-free tubulin polymerisation assays confirmed concentration-dependent inhibition of microtubule assembly across the series, and cell-cycle analysis revealed substituent-dependent redistribution consistent with an antimitotic mechanism, with several newly synthesised analogues producing stronger G2/M accumulation than colchicine under the selected assay conditions.
PMID:
42478157
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.
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