Quantum mechanics/molecular mechanics studies on the excited-state decay mechanisms of cytidine aza-analogues: 5-azacytidine and 2'-deoxy-5-azacytidine in aqueous solution.

The excited state properties and deactivation pathways of two DNA methylation inhibitors, , 5-azacytidine (5ACyd) and 2'-deoxy-5-azacytidine (5AdCyd) in aqueous solution, are comprehensively explored with the QM(CASPT2//CASSCF)/MM protocol. We systematically map the feasible decay mechanisms based on the obtained excited-state decay paths involving all the identified minimum-energy structures, conical intersections, and crossing points driving the different internal conversion (IC) and intersystem crossing (ISC) routes in and between the ππ*, nπ*, ππ*, nπ*, and S states. Unlike the nπ* state below the ππ* state in 5ACyd, deoxyribose group substitution at the N1 position leads to the ππ* state becoming the S state in 5AdCyd. In 5ACyd and 5AdCyd, the initially populated ππ* state mainly deactivates to the S state through the direct ππ* → S IC or mediated by the nπ* state. The former nearly barrierless IC channel of ππ* → S occurs ultrafast the nearby low-lying ππ*/S conical intersection. In the latter IC channel of ππ* → nπ* → S, the initially photoexcited ππ* state first approaches the nearby S/S conical section ππ*/nπ* and then undergoes efficient IC to the nπ* state, followed by the further IC to the initial S state the S/S conical intersection nπ*/S. The nπ*/S conical intersection is estimated to be located 6.0 and 4.9 kcal mol above the nπ* state minimum in 5ACyd and 5AdCyd, respectively, at the QM(CASPT2)/MM level. In addition to the efficient singlet-mediated IC channels, the minor ISC routes would populate ππ* to T(ππ*) through ππ* → T or ππ* → nπ* → T. Relatively, the ππ* → nπ* → T route benefits from the spin-orbit coupling (SOC) of nπ*/ππ* of 8.7 cm in 5ACyd and 10.2 cm in 5AdCyd, respectively. Subsequently, the T system will approach the nearby T/S crossing point ππ*/S driving it back to the S state. Given the ππ*/S crossing point located above the T minimum and the small T/S SOC, , 8.4 kcal mol and 2.1 cm in 5ACyd and 6.8 kcal mol and 1.9 cm in 5AdCyd, respectively, the slow T → S would trap the system in the T state for a while. The present work could contribute to understanding the mechanistic photophysics and photochemistry of similar aza-nucleosides and their derivatives.