Ruthenocenyl and 1-Adamantyl Paclitaxel Analogs Disrupt the Balance between βIII- and βIVa-Tubulin and Inhibit the...

Taxanes are widely used anticancer agents that stabilize microtubules and arrest cell division. However, their efficacy in colon cancer is limited by the chemoresistance associated with βIII-tubulin (TUBB3) upregulation. Herein, ferrocenyl, ruthenocenyl, and 1-adamantyl analogs of paclitaxel were synthesized and biologically evaluated. All compounds exhibited significantly higher cytotoxicity than paclitaxel, with IC₅₀ values in the nanomolar range. Ruthenocenyl and 1-adamantyl analogs effectively inhibited both growth and invasiveness of colon cancer cells. These effects correlated with altered tubulin isoform expression (downregulation of βIII-tubulin and upregulation of βIVa-tubulin) were associated with modulation of the focal adhesion complex. Specifically, changes in microtubule interactions with the integrin-linked kinase-integrin-β1 axis contributed to a reduced invasive potential. The unique properties of these analogs suggest their potential for dual-action therapy combining tumor growth inhibition with metastasis prevention.