Several small molecules targeting microtubule dynamics have been developed because microtubules are considered to be one of the most successful cancer chemotherapeutic targets. In this regard, taxol is most worthy to mention which stabilizes microtubule polymer thereby causing defectsinmitotic spindle assembly, chromosome segregation and cell division resulting in cancer inhibition. In this direction, we have earlier reported a small molecule called Pyrimidine‐Indole‐Hybrid (PIH (P)) which was found to inhibit ciliogenesis by inhibiting both the acetylation and polymerization of tubulin subunits. Here, we have evaluated the anticancer activities of PIH (P) and its water soluble derivatives. Three water soluble derivatives of PIH (P) namely 6 A, 6B and 6 C were synthesized. Among PIH (P) series of compounds, PIH (P) and 6 C were found to be the most potent compounds showing anti‐proliferative and cytoskeletal disrupting activities against MCF‐7 cells. Not only that, PIH (P) and 6 C also showed a promising effect in preventing cancer cell migration, invasion and colony‐formation and helped to reduce spheroid formation by several‐folds. They have potential to inhibit the activity of proteins (N‐Cadherin, Vimentin) responsible for Epithelial to Mesenchymal Transition (EMT). Hence, this class of compound could be a new antimitotic agent that is different from taxol with respect to mechanism, particularly by destabilizing tubulin rather than causing stabilization.

中文翻译：

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靶向微管蛋白的嘧啶吲哚杂化分子作为抗癌药的评估

已经开发了几种靶向微管动力学的小分子，因为微管被认为是最成功的癌症化学治疗靶标之一。在这方面，最值得一提的是紫杉醇，它可以稳定微管聚合物，从而引起有丝分裂纺锤体组装，染色体分离和细胞分裂的缺陷，从而抑制癌症。在这个方向上，我们较早地报道了一种称为嘧啶-吲哚-杂化（PIH（P））的小分子，该分子通过抑制微管蛋白亚基的乙酰化和聚合来抑制纤毛发生。在这里，我们评估了PIH（P）及其水溶性衍生物的抗癌活性。的三种水溶性衍生物合成了6 A，6B和6 C的PIH（P）。在PIH（P）系列化合物中，发现PIH（P）和6 C是最有效的化合物，显示出对MCF-7细胞的抗增殖和细胞骨架破坏活性。不仅如此，PIH（P）和6 C在预防癌细胞迁移，侵袭和集落形成方面也显示出有希望的作用，并帮助将球状体形成减少了几倍。它们可能会抑制负责上皮到间质转化（EMT）的蛋白质（N-钙黏着蛋白，波形蛋白）的活性。因此，这类化合物可以是一种新的抗有丝分裂剂，其作用机理与紫杉醇不同，尤其是通过使微管蛋白不稳定而不是引起稳定来实现。