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, i.e. , 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 1 ππ*, 1 nπ*, 3 ππ*, 3 nπ*, and S 0 states. Unlike the 1 nπ* state below the 1 ππ* state in 5ACyd, deoxyribose group substitution at the N1 position leads to the 1 ππ* state becoming the S 1 state in 5AdCyd. In 5ACyd and 5AdCyd, the initially populated 1 ππ* state mainly deactivates to the S 0 state through the direct 1 ππ* → S 0 IC or mediated by the 1 nπ* state. The former nearly barrierless IC channel of 1 ππ* → S 0 occurs ultrafast via the nearby low-lying 1 ππ*/S 0 conical intersection. In the latter IC channel of 1 ππ* → 1 nπ* → S 0 , the initially photoexcited 1 ππ* state first approaches the nearby S 2 /S 1 conical section 1 ππ*/ 1 nπ* and then undergoes efficient IC to the 1 nπ* state, followed by the further IC to the initial S 0 state via the S 1 /S 0 conical intersection 1 nπ*/S 0 . The 1 nπ*/S 0 conical intersection is estimated to be located 6.0 and 4.9 kcal mol -1 above the 1 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 1 ππ* to T 1 (ππ*) through 1 ππ* → T 1 or 1 ππ* → 1 nπ* → T 1 . Relatively, the 1 ππ* → 1 nπ* → T 1 route benefits from the spin-orbit coupling (SOC) of 1 nπ*/ 3 ππ* of 8.7 cm -1 in 5ACyd and 10.2 cm -1 in 5AdCyd, respectively. Subsequently, the T 1 system will approach the nearby T 1 /S 0 crossing point 3 ππ*/S 0 driving it back to the S 0 state. Given the 3 ππ*/S 0 crossing point located above the T 1 minimum and the small T 1 /S 0 SOC, i.e. , 8.4 kcal mol -1 and 2.1 cm -1 in 5ACyd and 6.8 kcal mol -1 and 1.9 cm -1 in 5AdCyd, respectively, the slow T 1 → S 0 would trap the system in the T 1 state for a while. The present work could contribute to understanding the mechanistic photophysics and photochemistry of similar aza-nucleosides and their derivatives.