A Theoretical Rationale why Furan‐side Monoadduct is More Favorable Toward Diadduct Formation in 8‐Methoxypsoralen and Thymine Complexes

Abstract

The photoinduced mechanism of formation of mono- and diadducts between 8-MOP and thymine bases is studied using the ONIOM(MPWB1K/6-31 + G(d,p):B3LYP/6-31G(d,p):UFF) and B3LYP/6-31 + G(d,p) methods. The relevant cycloaddition displays favorable energy barriers and reaction energies in the triplet excited state, which involves the initial formation of a diradical followed by ring closure via singlet-triplet interaction. The monoadduct on the pyrone side is favored over the furan side when comparing reaction energies. The distinguishing feature in the formation of the monoadducts is that the furan-side adduct displays a better photostability, which is a relatively high-barrier exothermic reaction, and thus the energy balance of the monoadduct on the furan side toward final diadduct formation is favored.

The Photoaddition of a Psoralen to DNA Proceeds via the Triplet State

“…The biradical 3 (AMT • −T • ) is thought to feature a single bond between the position 5′ of AMT and 6 of thymine. 25 The HOMO of AMT exhibits a large amplitude here and thus a substantial HOMO−HOMO interaction is possible. However, the LUMO of AMT has a very small amplitude here and therefore only a weak LUMO− LUMO interaction is expected.…”

“…In a DFT study for a biradical, closely related to 3 (AMT • −T • ), an energy difference of 57.7 kJ/mol between the singlet−triplet transition point and the equilibrium geometry of the biradical was computed. 25 With such an activation energy one expects lifetimes of the biradical of 0.1−1 ms depending on the pre-exponential factor. This magnitude is close to the one of the experimental value (∼50 μs).…”

“…24 This indicates that an alternative route to the adduct is taken. On the basis of DFT computation for the electronic ground state S 0 and the lowest triplet T 1 , Huang and Zhang 25 suggest that the furan-side adduct forms via a triplet biradical with one C−C single bond connecting the psoralen to the thymine moiety.…”

Photosensitization Reactions of Biomolecules: Definition, Targets and Mechanisms

“…It was shown from ONIOM and hybrid DFT calculations that the formation of furan‐ and pyrone‐side monoadducts to thymine involves a psoralens triplet excited state as the precursor of a biradical. In subsequent steps, a covalent bond is formed between either the furan or the pyrone moiety and C6 thymine before cyclobutane ring closure (209). Similar conclusions were reached for AMT, 8‐MOP, 5‐MOP and TMP from detailed studies including nanosecond UV‐vis and IR absorption spectroscopy together with IR computation (210,211).…”

Tracing the Photoaddition of Pharmaceutical Psoralens to DNA

“…The mechanism of this photoaddition was addressed by steady-state [11] and time-resolved spectroscopy [16][17][18] as well as quantum chemistry [19][20][21][22]. In a recent study, we traced the photo-addition of psoralen to DNA in real-time [23].…”