Ciszewski Wojciech M, Kowalczyk Karolina, Błauż Andrzej, Ciesielski Wojciech, Hogendorf Piotr, Smolarz Beata, Wagner Waldemar, Wieczorek-Błauż Anna, Rychlik Błażej Michał, Romanowicz Hanna, Durczyński Adam, Sobierajska Katarzyna, Plażuk Damian
Department of Molecular Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland.
Laboratory of Molecular Spectroscopy, Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, Lodz 91-403, Poland.
J Med Chem. 2025 Sep 25;68(18):19062-19075. doi: 10.1021/acs.jmedchem.5c01147. Epub 2025 Sep 4.
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 IC 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.
紫杉烷类是广泛使用的抗癌药物，可稳定微管并阻止细胞分裂。然而，它们在结肠癌中的疗效受到与βIII-微管蛋白（TUBB3）上调相关的化疗耐药性的限制。在此，合成了紫杉醇的二茂铁基、钌茂基和1-金刚烷基类似物并进行了生物学评估。所有化合物均表现出比紫杉醇显著更高的细胞毒性，IC值在纳摩尔范围内。钌茂基和1-金刚烷基类似物有效抑制了结肠癌细胞的生长和侵袭性。这些作用与微管蛋白亚型表达的改变（βIII-微管蛋白下调和βIVa-微管蛋白上调）相关，与粘着斑复合物的调节有关。具体而言，微管与整合素连接激酶-整合素-β1轴相互作用的变化导致侵袭潜能降低。这些类似物的独特性质表明它们具有将肿瘤生长抑制与转移预防相结合的双重作用疗法的潜力。
