Fully Reversible Photocontrol over DNA Intercalation with Visible Light

Here we present three novel photoswitchable DNA intercalators based on the diazocine scaffold. These compounds bind B-DNA in the trans state (K_D,trans = (4.14 ± 1.25)-(7.84 ± 3.41) × 10^-4 M) and show fully reversible "on"-"off" behavior upon visible-light irradiation without any sign of fatigue over six cycles. The affinity of the trans state is at least 1000-fold higher than of the cis state. The ability to reversibly turn off all observable binding with in situ visible light irradiation is so far unmatched in the literature. Preliminary cytotoxicity studies of 3,3'-dimethanamine-diazocine (3) show negligible dark toxicity (EC₅₀ > 100 μM) with a significant increase upon irradiation (395 nm, EC₅₀ = 45.4 μM, PI > 2) in HeLa cells, allowing for spatiotemporal control of activity in photopharmacology applications.