Photoswitchable formation of a DNA interstrand cross-link by a coumarin-modified nucleotide

A coumarin-modified pyrimidine nucleoside (1) has been synthesized using a Cu^I-catalyzed click reaction and incorporated into oligodeoxynucleotides (ODNs). Interstrand cross-links are produced upon irradiation of ODNs containing 1 at 350 nm. Cross-linking occurs through a [2+2] cycloaddition reaction with the opposing thymidine, 2'-deoxycytidine, or 2'-deoxyadenosine. A much higher reactivity was observed with dT than dC or dA. Irradiation of the dT-1 and dC-1 cross-linked products at 254 nm leads to a reversible ring-opening reaction, while such phenomena were not observed with dA-1 adducts. The reversible reaction is ultrafast and complete within 50-90 s. Consistent photoswitching behavior was observed over 6 cycles of irradiation at 350 nm and 254 nm. To the best of our knowledge, this is the first example of photoswitchable interstrand cross-linking formation induced by a modified pyrimidine nucleoside. A [2+2] cycloaddition reaction between a coumarin-modified pyrimidine nucleoside and the opposing thymidine, 2'-deoxycytidine, or 2'-deoxyadenosine on a DNA strand generates photoswitchable interstrand cross-links (ICLs) in the DNA.