Triplet Decay Dynamics in Sulfur-Substituted Thymine: How Position of Substitution Matters

Abstract

Sulfur-substituted analogues of thymine are of three types depending on the position of sulfur substitution: 2-thiothymine (2tThy), 4-thothymine (4tThy), and 2,4dithiothymine (dtThy). These molecules, on photoexcitation, are known to form in their triplet state with near unity yield. Consequently, they are able to photosensitize ground state molecular oxygen to singlet oxygen, a property which makes them potential drugs for photodynamic therapy (PDT). The singlet oxygen yield is directly correlated with the triplet lifetime of the thiothymine, which in turn is governed by its triplet decay dynamics. In this work, the dependence of the triplet decay dynamics on the position of sulfur substitution is investigated by comparatively studying all three thiothymines. The topology of the triplet potential energy surface and decay mechanism of 2tThy is found to be distinctly different from 4tThy and dtThy. The fundamental reason for this is the different electronic natures of the two CX (X = O, S) moieties in each molecule, one of which is conjugated with a CC bond, while the other is not. Further, it is shown that the triplet lifetime of 2tThy can be increased by manipulating the energetic ordering of its molecular orbitals with unobtrusive substitutions, thus making it a better candidate for a PDT drug.

Quantum effects in photosensitization: The case of singlet oxygen generation by thiothymines

“…It is interesting that 2tThy and 4tThy, two very similar molecules, have such different electronic properties so as to warrant different approaches to calculating the rate at which they photosensitize O 2 . Also, 4tThy and dtThy are similar to each other, while being different to 2tThy, pointing to a position-dependent effect at play [38,47].…”

“…The main structural difference between T ring 1 and T pyr 1 is strong pyramidalization of the carbonyl or thionyl group at C 2 . For 4tThy and dtThy, the T pyr 1 minimum is considerably high in energy and inaccessible, whereas a small energy difference exists between T ring 1 and T pyr 1 in 2tThy, making both structures relevant [38,47]. As noted earlier, since ISC rates are fast [18] and triplet lifetimes are long [19,20], ISC will not be a determining factor in calculating photosensitization rate constants.…”

“…Based on previous studies which find one of the thiothymines, 2tThy, to have a double well in its T 1 potential energy surface, we consider 2 triplet minima for this molecule (structures denoted as T ring 1 and T pyr 1 ) and the one relevant minimum for 4tThy and dtThy, which is the T ring 1 structure (Fig. S3) [38,[44][45][46]. The main structural difference between T ring 1 and T pyr 1 is strong pyramidalization of the carbonyl or thionyl group at C 2 .…”

“…Serrano-Andres and coworkers showed that diabatic coupling is maximized with orbital overlap. [15] Further, the nature of the lowest triplet state in all 3 thiothymines was found to be ππ * [38]. Therefore, we have chosen three approach directions (shown in Fig.…”

Excited States of Thio-2′-deoxyuridine Bearing an Extended π-Conjugated System: 3′,5′-Di-O-acetyl-5-phenylethynyl-4-thio-2′-deoxyuridine

“…[5][6][7][8][9][10][11][12][13][14][15][16] Whereas the relaxation process of native nucleosides in the excited singlet state is known to be ultrafast internal conversion (IC) to the ground state (the lifetime in the excited singlet state was reported to be within 1 ps), [17][18][19] that of thionucleosides is highly efficient intersystem crossing (ISC) to the triplet manifolds, triggered by the thiocarbonyl group. [5][6][7][8][9][10][11][12][20][21][22][23][24][25][26][27][28][29][30][31][32][33] The triplet thionucleosides enable effective triplet energy transfer and/or electron transfer to generate singlet molecular oxygen ( 1 O 2 * ), superoxide and other oxygen radical species through the photosensitization reaction, [5][6][7][8][9][10][11][12] eventually causing cell death. [34]…”