Design and assessment of photoactivatable anthracene-based DNA interstrand cross-linkers for light-controlled...

Anthracene, a well-established DNA intercalator, offers a distinctive platform for the development of light-responsive DNA cross-linking agents due to its strong binding affinity to nucleic acids, efficient photoexcitation properties, and capacity to generate reactive intermediates. Building on these attributes, we synthesized five 9,10-dimethylanthracene derivatives (1a-e) functionalized with diverse leaving groups to evaluate their capability for producing DNA interstrand cross-links (ICL) upon UV activation. The structural variations were designed to modulate reactivity, cross-linking efficiency, and cellular toxicity. Among these, derivative 1b, incorporating a trimethylammonium moiety, achieved the highest ICL formation yield (40 %) and exhibited the most rapid cross-linking kinetics under aqueous conditions. Mechanistic investigations indicated that the light-triggered reactions proceed through a combination of radical and carbocation pathways, with carbocations playing a dominant role in facilitating ICL events. This study introduces a novel class of anthracene-based compounds capable of forming DNA ICLs upon photoactivation. Biological assays revealed that all compounds gained substantial cytotoxic potency following UV exposure, with 1e bearing a morpholine group displays nanomolar-level IC₅₀ values and superior selectivity. Alkaline comet assays confirmed that light irradiation significantly increased DNA damage in cancer cells treated with 1b, 1d, and 1e, supporting their potential as candidates for light-controlled anticancer therapies. Overall, these results underscore the promise of anthracene derivatives as tunable photochemical tools for targeted cancer treatment.