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

Abstract

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 ¹ππ*, ¹nπ*, ³ππ*, ³nπ*, and S₀ states. Unlike the ¹nπ* state below the ¹ππ* state in 5ACyd, deoxyribose group substitution at the N1 position leads to the ¹ππ* state becoming the S₁ state in 5AdCyd. In 5ACyd and 5AdCyd, the initially populated ¹ππ* state mainly deactivates to the S₀ state through the direct ¹ππ* → S₀ IC or mediated by the ¹nπ* state. The former nearly barrierless IC channel of ¹ππ* → S₀ occurs ultrafast via the nearby low-lying ¹ππ*/S₀ conical intersection. In the latter IC channel of ¹ππ* → ¹nπ* → S₀, the initially photoexcited ¹ππ* state first approaches the nearby S₂/S₁ conical section ¹ππ*/¹nπ* and then undergoes efficient IC to the ¹nπ* state, followed by the further IC to the initial S₀ state via the S₁/S₀ conical intersection ¹nπ*/S₀. The ¹nπ*/S₀ conical intersection is estimated to be located 6.0 and 4.9 kcal mol⁻¹ above the ¹nπ* 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 ¹ππ* to T₁(ππ*) through ¹ππ* → T₁ or ¹ππ* → ¹nπ* → T₁. Relatively, the ¹ππ* → ¹nπ* → T₁ route benefits from the spin–orbit coupling (SOC) of ¹nπ*/³ππ* 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 ³ππ*/S₀ driving it back to the S₀ state. Given the ³ππ*/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 → 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.