A comprehensive review and recent advances on isatin-based compounds as a versatile framework for anticancer...

Isatin (1H-indole-2,3-dione) is a privileged nitrogen-containing heterocyclic framework that has received considerable attention in anticancer drug discovery owing to its general biological behavior and structural diversity. This review focuses on isatin-heterocyclic hybrids as a valuable model in the development of new anti-cancer drugs that may reduce side effects and help overcome drug resistance, discussing their synthetic approaches and mechanism of action as apoptosis induction through kinase inhibition. With various chemical modifications, isatin had an excellent ability to build powerful isatin hybrids and conjugates targeting multiple oncogenic pathways. It is worth mentioning that isatin-hybrids exhibited anticancer activity against various cancer cell lines, such as breast, liver, colon, lung, and multidrug-resistant carcinomas. Their mechanisms include mitochondrial-mediated apoptosis, caspase activation, tubulin polymerization inhibition, and kinase modulation, particularly VEGFR-2, EGFR, CDK2, and STAT-3. Numerous synthesized isatin-based compounds have shown superior cytotoxicity compared to established chemotherapeutics, with favorable IC₅₀ values and minimal toxicity toward normal cells. In addition, this review summarizes more recent synthetic innovations, e.g., microwave-assisted and multi-component techniques, which offer improved pharmacological profiles of these isatin-heterocyclic hybrids with improved cytotoxicity and target signaling pathways. Overall, these results underscore the value of isatin as a flexible scaffold for the rational design of new anticancer agents. To increase bioavailability and targeted delivery, especially in solid tumors, and to lead to the creation of novel, potent anticancer therapies, nano-formulation drug delivery systems with revolutionary drug signaling pathways will be further advocated in the future.