Ebenezer Oluwakemi, Shapi Michael, Tuszynski Jack A
Department of Chemistry, Faculty of Natural Science, Mangosuthu University of Technology, Umlazi 4031, South Africa.
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
Int J Mol Sci. 2022 Apr 4;23(7):4001. doi: 10.3390/ijms23074001.
Microtubules are cylindrical protein polymers formed from -tubulin heterodimers in the cytoplasm of eukaryotic cells. Microtubule disturbance may cause cell cycle arrest in the G2/M phase, and anomalous mitotic spindles will form. Microtubules are an important target for cancer drug action because of their critical role in mitosis. Several microtubule-targeting agents with vast therapeutic advantages have been developed, but they often lead to multidrug resistance and adverse side effects. Thus, single-target therapy has drawbacks in the effective control of tubulin polymerization. Molecular hybridization, based on the amalgamation of two or more pharmacophores of bioactive conjugates to engender a single molecular structure with enhanced pharmacokinetics and biological activity, compared to their parent molecules, has recently become a promising approach in drug development. The practical application of combined active scaffolds targeting tubulin polymerization inhibitors has been corroborated in the past few years. Meanwhile, different designs and syntheses of novel anti-tubulin hybrids have been broadly studied, illustrated, and detailed in the literature. This review describes various molecular hybrids with their reported structural-activity relationships (SARs) where it is possible in an effort to generate efficacious tubulin polymerization inhibitors. The aim is to create a platform on which new active scaffolds can be modeled for improved tubulin polymerization inhibitory potency and hence, the development of new therapeutic agents against cancer.
微管是由α-微管蛋白异二聚体在真核细胞胞质中形成的圆柱形蛋白质聚合物。微管紊乱可能导致细胞周期停滞在G2/M期，并会形成异常的有丝分裂纺锤体。由于微管在有丝分裂中起关键作用，因此它是癌症药物作用的重要靶点。已经开发出几种具有巨大治疗优势的微管靶向剂，但它们常常导致多药耐药性和不良副作用。因此，单靶点治疗在有效控制微管蛋白聚合方面存在缺陷。分子杂交是将两种或更多种生物活性缀合物的药效基团合并，以产生一种与母体分子相比具有增强的药代动力学和生物活性的单一分子结构，最近已成为药物开发中一种很有前景的方法。在过去几年中，靶向微管蛋白聚合抑制剂的联合活性支架的实际应用已得到证实。同时，新型抗微管蛋白杂化物的不同设计和合成已在文献中得到广泛研究、说明和详述。本综述描述了各种分子杂化物及其报道的构效关系（SARs），旨在努力开发有效的微管蛋白聚合抑制剂。目的是创建一个平台，在该平台上可以构建新的活性支架，以提高微管蛋白聚合抑制效力，从而开发新的抗癌治疗药物。
