Work

Ruthenocenyl and 1-Adamantyl Paclitaxel Analogs Disrupt the Balance between βIII- and βIVa-Tubulin and Inhibit the Growth and Invasiveness of Colon Cancer

Year: 2025

Type: article

Abstract: 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c01147