Tunable and Photoactivatable Mimics of Calicheamicin γ₁ for DNA Cleavage.

ABSTRACT: 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

SUBMITTER: Ben-Zvi B 

PROVIDER: S-EPMC11421022 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature