Microtubule targeting agents (MTAs) are among the most successful chemotherapeutic drugs, but their efficacy is often limited by the development of multidrug resistance (MDR). Therefore, the development of novel MTAs with the ability to overcome MDR is urgently needed. In this contribution, through modification of the unsymmetric biaryl compounds, we discovered a novel compound dxy-1-175 with potent anti-proliferative activity against cancer cells. Mechanistic study revealed that dxy-1-175 inhibited tubulin polymerization by interacting with the colchicine-binding site of tubulin, which caused cell cycle arrest at G₂/M phase. Based on the predicted binding model of dxy-1-175 with tubulin, a series of new 4-benzoylbiphenyl analogues were designed and synthesized. Among them, the hydrochloride compound 12e with improved solubility and good stability in human liver microsome, exhibited the most potent anti-proliferative activity with IC₅₀ value in the low nanomolar range, and markedly inhibited the growth of breast cancer 4T1 xenograft in vivo. Notably, 12e effectively overcame P-gp-mediated MDR and our preliminary data suggested that 12e may not be a substrate of P-glycoprotein (P-gp). Taken together, our study reveals a novel MTA 12e targeting the colchicine-binding site with potent anticancer activity and the ability to circumvent MDR.

微管靶向剂 (MTA) 是最成功的化疗药物之一，但其疗效通常受到多药耐药性 (MDR) 的发展的限制。因此，迫切需要开发具有克服 MDR 能力的新型 MTA。在这项贡献中，通过对不对称联芳基化合物的修饰，我们发现了一种具有有效抗癌细胞增殖活性的新型化合物dxy-1-175 。机理研究表明，dxy-1-175通过与微管蛋白的秋水仙碱结合位点相互作用来抑制微管蛋白聚合，从而导致细胞周期停滞在 G ₂ /M 期。基于dxy-1-175的预测结合模型使用微管蛋白，设计并合成了一系列新的4-苯甲酰基联苯类似物。其中，盐酸盐化合物12e在人肝微粒体中具有改善的溶解度和良好的稳定性，在低纳摩尔范围内表现出最强的IC ₅₀值的抗增殖活性，并且在体内显着抑制了乳腺癌4T1异种移植物的生长。值得注意的是，12e有效地克服了 P-gp 介导的 MDR，我们的初步数据表明12e可能不是 P-糖蛋白 (P-gp) 的底物。总之，我们的研究揭示了一种新的 MTA 12e，它靶向秋水仙碱结合位点，具有强大的抗癌活性和规避 MDR 的能力。