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 & PRIME;-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 & pi;& pi;*, 1n & pi;*, 3 & pi;& pi;*, 3n & pi;*, and S0 states. Unlike the 1n & pi;* state below the 1 & pi;& pi;* state in 5ACyd, deoxyribose group substitution at the N1 position leads to the 1 & pi;& pi;* state becoming the S1 state in 5AdCyd. In 5ACyd and 5AdCyd, the initially populated 1 & pi;& pi;* state mainly deactivates to the S0 state through the direct 1 & pi;& pi;* & RARR; S0 IC or mediated by the 1n & pi;* state. The former nearly barrierless IC channel of 1 & pi;& pi;* & RARR; S0 occurs ultrafast via the nearby low-lying 1 & pi;& pi;*/S0 conical intersection. In the latter IC channel of 1 & pi;& pi;* & RARR; 1n & pi;* & RARR; S0, the initially photoexcited 1 & pi;& pi;* state first approaches the nearby S2/S1 conical section 1 & pi;& pi;*/1n & pi;* and then undergoes efficient IC to the 1n & pi;* state, followed by the further IC to the initial S0 state via the S1/S0 conical intersection 1n & pi;*/S0. The 1n & pi;*/S0 conical intersection is estimated to be located 6.0 and 4.9 kcal mol-1 above the 1n & pi;* 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 & pi;& pi;* to T1(& pi;& pi;*) through 1 & pi;& pi;* & RARR; T1 or 1 & pi;& pi;* & RARR; 1n & pi;* & RARR; T1. Relatively, the 1 & pi;& pi;* & RARR; 1n & pi;* & RARR; T1 route benefits from the spin-orbit coupling (SOC) of 1n & pi;*/3 & pi;& pi;* of 8.7 cm-1 in 5ACyd and 10.2 cm-1 in 5AdCyd, respectively. Subsequently, the T1 system will approach the nearby T1/S0 crossing point 3 & pi;& pi;*/S0 driving it back to the S0 state. Given the 3 & pi;& pi;*/S0 crossing point located above the T1 minimum and the small T1/S0 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 T1 & RARR; S0 would trap the system in the T1 state for a while. The present work could contribute to understanding the mechanistic photophysics and photochemistry of similar aza-nucleosides and their derivatives. The excited state properties and deactivation pathways of two DNA methylation inhibitors, i.e., 5-azacytidine (5ACyd) and 2 & PRIME;-deoxy-5-azacytidine (5AdCyd) in aqueous solution are comprehensively explored with the QM(CASPT2//CASSCF)/MM protocol.