Tunable\nand Photoactivatable Mimics of Calicheamicin\nγ<sub>1</sub> for DNA Cleavage

Calicheamicin γ<sub>1</sub> and related natural\nproducts\nare renowned for their potency in DNA cleavage, serving as the warheads\nin commercial ADCs used for treating leukemia. Their mechanism of\naction involves the formation of aryl radicals, which abstract hydrogen\natoms from nucleic acids. However, the complex strained enediyne structure\nof calicheamicin γ<sub>1</sub> presents significant challenges\nin synthesis, resulting in high production costs and limited structural\nand activity modularity for tuning the therapeutic window. This report\ndescribes the development of simple molecular mimics based on diazonium\nsalts, synthesized in fewer than 3 steps, capable of generating aryl\nradicals upon green or red light irradiation. SAR studies conducted\non over 30 analogues reveal a wide range of potencies in DNA cleavage,\nwith EC<sub>50</sub> values ranging from low nanomolar to micromolar.\nForming benzenoid diradicals does not appear to be necessary for potent\nDNA cleavage; instead, DNA cleavage can be achieved with radicals\ndistributed among different arenes when connected with proper linkages.\nThe potency is influenced by electronic effects, stereochemistry,\norbital orientations, the distance between multiradicals, and the\nnumber of diazonium motifs within the molecule. In addition to providing\na more cost-effective, efficient, and modular alternative to calicheamicin\nγ<sub>1</sub>, this technology offers the potential for enhanced\nspecificity through spatiotemporal control.