Base Oxidation at 5′ Site of GG Sequence in Double-stranded DNA Induced by UVA in the Presence of Xanthone Analogues: Relationship Between the DNA-damaging Abilities of Photosensitizers and Their HOMO Energies¶

Abstract

UVA contributes to skin cancer by solar UV light. Photosensitizers are believed to play an important role in UVA carcinogenesis. We investigated the mechanism of DNA damage induced by photoexcited xanthone (XAN) analogues (XAN, thioxanthone [TXAN] and acridone [ACR]), exogenous photosensitizers, and the relationship between the DNA-damaging abilities and their highest occupied molecular orbital (HOMO) energies. DNA damage by these photosensitizers was examined using 32P-labeled DNA fragments obtained from the p53 tumor suppressor gene. Photoexcited XAN caused DNA cleavage specifically at 5'-G of the GG sequence in the double-stranded DNA only when the DNA fragments were treated with piperidine, suggesting that DNA cleavage is due to base modification with little or no strand breakage. With denatured single-stranded DNA, the extent of XAN-sensitized photodamage was decreased. An oxidative product of G, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo), was formed by photoexcited XAN, and the 8-oxo-dGuo formation was decreased in single-stranded DNA. TXAN and ACR induced DNA photodamage as did XAN, although the order of DNA-damaging ability was XAN > TXAN > ACR. These findings suggest that photoexcited XAN analogues induce nucleobase oxidation at 5'-G of GG sequence in double-stranded DNA through electron transfer. The HOMO energies of these photosensitizers, estimated from ab initio molecular orbital (MO) calculation, decreased in the following order: XAN > TXAN > ACR. Extents of DNA damage increased exponentially with the HOMO energies of XAN analogues. This study suggests that DNA-damaging abilities of photosensitizers can be estimated from their HOMO energies.

Theoretical Study on Reactions of Triplet Excited State Thioxanthone with Indole

“…As INH possesses higher E T1 relative to TX, the direct energy transfer based deactivation pathway is unfeasible. Moreover, it is worth mentioning that as E T1 of TX is higher than the energy needed to bring 3 O 2 to singlet excited state ( 1 O 2 ), 1.05 eV ${false(}^3{\sum }_g^{-}\to {\Delta }_{\text{g}}^1)$ or 1.65 eV ${(}^3{\sum }_g^{-}{\to }^1{\sum }_g^{+}false)$, through direct energy transfer T 1 state TX can photogenerate singlet oxygen ( 1 O 2 ), which may be involved in the DNA photooxidation by TX [4]: $\text{TX}false({\text{T}}_{1}false){+}^3{\text{O}}_2\to \text{TX}{+}^1{\text{O}}_2$…”

“…In contrast, the electron transfer from T 1 state TX to INH (Equation 4) is theoretically unfeasible because of the positive value of total reaction energy (summation of AIP T1 of TX and AEA of INH). In previous study, the electron transfer-based DNA oxidation by photoexcited TX has been reported [4]. The electron transfer process has also been reported to be involved in the deactivation of T 1 state TX by amines or indolic derivatives [7,8].…”

“…It has been reported that photoexcited TX can cause DNA damage [4]. It is known that photosensitization involves two mechanisms, i.e., direct reaction with substrates ( e.g., DNA, amino acids and proteins) (Type I) or damage via intermediacy of oxygen (through energy or electron transfer processes with molecular oxygen to generate toxic reactive oxygen species) (Type II).…”

Studies on reaction of amino acids and triplet thioxanthone derivatives by laser flash photolysis

“…Their studies suggested that photo-excited TX induce nucleotide oxidation at 5 -G of GG sequence in doublestranded DNA via electron transfer. Potential mechanisms of action may include DNA intercalation, inhibition of nucleic acid biosynthesis as well as formation of intracellular DNA single strand breaks [11]. So far, the exact mechanism of anti-tumor action of TXs is unclear yet.…”

Antioxidant Activity of Caffeic Acid through a Novel Mechanism under UVA Irradiation

“…Photosensitizers, xanthone and its derivatives have been extensively examined for the UVA-induced DNA damage [9, 10]. It has been also known that xanthone mediates the photosensitized decomposition of fatty ester hydroperoxides to produce oxyl radicals [11] and hydroxyl radicals [12].…”