1,2,3-Triazole-Indole Derived Hybrids: Recent Progress and Therapeutic Perspectives for Cancer Treatment.

1,2,3-Triazole and indole-derived scaffolds are privileged nitrogen-containing heterocyclic pharmacophores that form abundant non-covalent interactions with tumor-related biomacromolecules. Molecular hybridization that integrates these two scaffolds into a single molecular scaffold yields 1,2,3-triazole-indole-derived hybrids, which can mitigate intrinsic drawbacks of single-heterocycle anticancer small-molecule agents, such as insufficient target selectivity, unsatisfactory pharmacokinetic performance, and acquired multidrug resistance. This review summarizes research advances on 1,2,3-triazole-indole-derived anticancer hybrids published from 2021 to the present, and the structure-activity relationships (SARs) as well as modes of action are discussed. These hybrids exert broad-spectrum multi-target anticancer effects through kinase inhibition, cell-cycle arrest, caspase-dependent apoptosis, anti-angiogenic and anti-migratory activities, tubulin polymerization disruption, as well as modulation of autophagy, immunogenic cell death, and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling axis. Representative candidates exhibit robust in vitro antiproliferative potency against diverse cancer cell lines, favorable selectivity toward normal human cells, satisfactory plasma metabolic stability, and potent in vivo tumor growth inhibitory effects. This comprehensive overview provides systematic theoretical guidance and rational design principles for further development and clinical translation of high-efficiency, low-toxicity 1,2,3-triazole-indole-derived hybrid lead compounds for precise therapy against cancers.