A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization

Microtubules are cylindrical protein polymers formed from alpha beta-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.

Automated summary

Microtubules are important protein polymers in eukaryotic cells, and their disturbance can cause cell cycle arrest and abnormal mitotic spindles. Targeting microtubules has been a focus in cancer drug development, but single-target therapy has limitations. Molecular hybridization has emerged as a promising approach to improve the efficacy of tubulin polymerization inhibitors. This review summarizes the design and synthesis of various molecular hybrids and discusses their structure-activity relationships.