Tunable and Photoactivatable Mimics of Calicheamicin γ₁ for DNA Cleavage

Calicheamicin γ₁ and related natural products are renowned for their potency in DNA cleavage, serving as the warheads in commercial ADCs used for treating leukemia. Their mechanism of action involves the formation of aryl radicals, which abstract hydrogen atoms from nucleic acids. However, the complex strained enediyne structure of calicheamicin γ₁ presents significant challenges in synthesis, resulting in high production costs and limited structural and activity modularity for tuning the therapeutic window. This report describes the development of simple molecular mimics based on diazonium salts, synthesized in fewer than 3 steps, capable of generating aryl radicals upon green or red light irradiation. SAR studies conducted on over 30 analogues reveal a wide range of potencies in DNA cleavage, with EC₅₀ values ranging from low nanomolar to micromolar. Forming benzenoid diradicals does not appear to be necessary for potent DNA cleavage; instead, DNA cleavage can be achieved with radicals distributed among different arenes when connected with proper linkages. The potency is influenced by electronic effects, stereochemistry, orbital orientations, the distance between multiradicals, and the number of diazonium motifs within the molecule. In addition to providing a more cost-effective, efficient, and modular alternative to calicheamicin γ₁, this technology offers the potential for enhanced specificity through spatiotemporal control.