Bioorthogonal Cyclization Reactions for the Synthesis of Cytotoxic Drugs in Cancer Treatment

Cyclization reactions play a central role in the synthesis of heterocycles, many of which display potent cytotoxicity and are actively being developed as anticancer agents. Recent breakthroughs have enabled these transformations to occur in situ within living systems, thereby advancing novel bioorthogonal strategies for spatially controlled cancer therapies. This strategy enhances therapeutic efficacy by promoting the localized formation of active drugs at tumor sites, significantly reducing systemic toxicity and off-target effects. Herein, we review recent advances in the use of bioorthogonal cyclization reactions to generate cytotoxic (hetero)-cycles, including triazoles, benzotriazoles, phenanthridines, phenanthridinium salts, quinoxalines, coumarins, naphthalenes, and pyrrolizidine derivatives, directly within cancer cells. We examine the cyclization reaction classes employed, the triggers (e.g., transition metals, light, and reactive oxygen species), underlying mechanisms, and bioorthogonal strategies enabling these transformations. This Mini Review offers a focused overview of state-of-the-art methods and their therapeutic applications and highlights the transformative potential of in situ cyclization as a platform for developing next-generation, highly efficient anticancer therapies.