Mutai Peggoty, Breuzard Gilles, Pagano Alessandra, Allegro Diane, Peyrot Vincent, Chibale Kelly
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Department of Pharmacology & Pharmacognosy, College of Health Sciences, University of Nairobi, PO Box 19676-00202, Nairobi, Kenya.
Aix-Marseille Université, INSERM UMR_S 911 CRO2, Faculté de Pharmacie, 27 bd Jean-Moulin, 13385 Marseille, France.
Bioorg Med Chem. 2017 Mar 1;25(5):1652-1665. doi: 10.1016/j.bmc.2017.01.035. Epub 2017 Jan 27.
The synthesis of twenty-six 4-arylcoumarin analogues of combretastatin A-4 (CA-4) led to the identification of two new compounds (25 and 26) with strong cytotoxic activity. Both compounds had a high cytotoxic effect on a CA-4-resistant colon adenocarcinoma cell line (HT29D4). The compounds affected cell cycle progression characterized by a mitotic block. The activity of these compounds against microtubules both in vitro and in cells was examined and both compounds were found to potently inhibit in vitro microtubule formation via a sub-stoichiometric mode like CA-4. By immunofluorescence, it was observed that both compounds induced strong microtubule network disruption. Our results provide a strong experimental basis to develop new potent anti-tubulin molecules targeting CA-4-resistant cancer cells.
对26种康普他汀A-4（CA-4）的4-芳基香豆素类似物进行合成，从而鉴定出两种具有强细胞毒性活性的新化合物（25和26）。这两种化合物对一种CA-4耐药结肠腺癌细胞系（HT29D4）具有高细胞毒性作用。这些化合物影响细胞周期进程，其特征为有丝分裂阻滞。检测了这些化合物在体外和细胞中对微管的活性，发现这两种化合物都像CA-4一样通过亚化学计量模式有效抑制体外微管形成。通过免疫荧光观察到，这两种化合物均诱导强烈的微管网络破坏。我们的结果为开发针对CA-4耐药癌细胞的新型强效抗微管蛋白分子提供了有力的实验依据。
