Electronic Structure Engineering at C7 Position of Thieno-Cytosine (thC): Toward Optimal Probe-Adduct Interactions...

N'-(2'-deoxyguanosin-8-yl)-4-aminobiphenyl (ABPG) is a well-established carcinogenic DNA adduct identified in the human body, rendering its detection a critical research priority. To achieve highly selective sensing of ABPG, we theoretically designed a series of novel nucleobase analogues derived from thC (D. Shin, R. W. Sinkeldam, and Y. Tor, J. Am. Chem. Soc., 2011, 133, 14912-14915). These analogues feature systematic substitutions at the C7 position with electron-donating groups (-CH3, -OH, -OCH3) and electron-withdrawing groups (-COOH, -CN, -NO2). Their photophysical properties were systematically evaluated using TDDFT methods. The results indicate that these probes exhibit significantly redshifted absorption and distinct environment-dependent fluorescence behavior. Notably, their emission remains stable upon pairing with complementary natural guanine (G). In contrast, when forming Watson-Crick (WC) base pairs with the target ABPG adduct, an efficient excited-state intermolecular charge transfer (ESICT) process is triggered, specifically for the -CN and -NO2 modified thC analogues, leading to pronounced fluorescence quenching and thereby enabling a selective signal-off response for ABPG recognition. To better mimic real nucleic acid contexts, the optimal probe was further conjugated with deoxyribose to construct the corresponding nucleoside analogue. The results confirm that the core photophysical mechanism remains effective within the nucleoside framework. By integrating the favorable fluorescence properties of modified thC motifs with the high selectivity enabled by the ESICT mechanism, this work provides a theoretical foundation and a molecular design strategy for developing quasi-intrinsic fluorescent probes that can be incorporated into DNA strands for the in situ detection of carcinogenic DNA adducts.