2,4-Dithiothymine as a Potent UVA Chemotherapeutic Agent

Abstract

Substitution of both oxygen atoms in the exocyclic carbonyl groups of the thymine chromophore by sulfur atoms results in a remarkable redshift of its absorption spectrum from an absorption maximum at 267 nm in thymidine to 363 nm in 2,4-dithiothymine (ΔE = 9905 cm(-1)). A single sulfur substitution of a carbonyl group in the thymine chromophore at position 2 or 4 results in a significantly smaller redshift in the absorption maximum, which depends sensitively on the position at which the sulfur atom is substituted, varying from 275 nm in 2-thiothymine to 335 nm in 4-thiothymidine. Femtosecond transient absorption spectroscopy reveals that excitation of 2,4-dithiothymine at 335 or 360 nm leads to the ultrafast population of the triplet state, with an intersystem crossing lifetime of 180 ± 40 fs—the shortest intersystem crossing lifetime of any DNA base derivative studied so far in aqueous solution. Surprisingly, the degree and position at which the sulfur atom is substituted have important effects on the magnitude of the intersystem crossing rate constant, showing a 1.2-, 3.2-, and 4.2-fold rate increases for 2-thiothymine, 4-thiothymidine, and 2,4-dithiothymine, respectively, relative to that of thymidine, whereas the triplet yield increases 60-fold to near unity, independent of the site of sulfur atom substitution. While the natural thymine monomers owe their high degree of photostability to ultrafast internal conversion to the ground state and low triplet yields, the near-unity triplet yields in the thiothymine series account for their potent photosensitization properties. Nanosecond time-resolved luminescence spectroscopy shows that 4-thiothymidine and 2,4-dithiothymine are efficient singlet oxygen generators, with singlet oxygen quantum yields of 0.42 ± 0.02 and 0.46 ± 0.02, respectively, in O2-saturated acetonitrile solution. Taken together, these photophysical measurements strongly suggest that 2,4-dithiothymine can act as a more effective UVA chemotherapeutic agent than the currently used 4-thiothymidine, especially in deeper-tissue chemotherapeutic applications.

Triplet state formation and quenching dynamics of 2-mercaptobenzothiazole in solution

“…14,15 Ultrafast thione T1 state formation dynamics have been investigated by TEAS, as well as by ab initio electronic structure calculations and surface hopping simulations that include spin-orbit coupling. [16][17][18][19][20][21][22][23][24][25][26][27] The emerging picture is of a complicated competition between IC and efficient ISC.…”

Oxidatively-generated damage to DNA and proteins mediated by photosensitized UVA

“…In contrast to 6-TG, ROS do not appear to contribute significantly to the phototoxicity of S 4 dT at low UVA doses [62]. Paradoxically, however, UVA irradiation of S 4 dT in solution yielded similar (or higher) 1 O 2 yields to irradiated 6-TG [26], [63].…”

“…In contrast to 6-TG, ROS do not appear to contribute significantly to the phototoxicity of S 4 dT at low UVA doses [62]. Paradoxically, however, UVA irradiation of S 4 dT in solution yielded similar (or higher) 1 O 2 yields to irradiated 6-TG [26], [63]. Halothiopyrimidines UVA degrades SIdU both in free solution and in DNA. An initial UVA-induced deiodination gives rise to a thiouracil-5-yl radical that can be further converted to SdU.…”

“…DNA S 4 T is, however, extremely cytotoxic in combination with low doses of UVA [24]. Recently, 2,4-dithiothymidine has been shown to be comparable or superior to 4-thiothymidine as a photosensitiser in solution and it is cytotoxic in combination with UVA [26], [27].The halopyrimidine nucleosides 5-iodo-2′-deoxyuridine (IdU) and 5-bromo-2′-deoxyuridine (BrdU) are also thymidine analogs. They are used extensively to label DNA where they can be detected by fluorescent antibodies or by an induced shift in DNA buoyant density.…”

“…DNA S 4 T is, however, extremely cytotoxic in combination with low doses of UVA [24]. Recently, 2,4-dithiothymidine has been shown to be comparable or superior to 4-thiothymidine as a photosensitiser in solution and it is cytotoxic in combination with UVA [26], [27].…”