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

Abstract

Psoralens are natural compounds that serve in the light dependent treatment of certain skin diseases (PUVA therapy). They are DNA intercalators that upon photoexcitation form adducts with thymine bases. For one psoralen derivative, 4′-aminomethyl-4,5′,8-trimethylpsoralen (AMT), the photoreactions are characterized here by nanosecond UV–vis and IR absorption spectroscopy. The triplet state of AMT is identified as the reactive one. On the 1–10 μs time scale this local triplet state transforms into a triplet biradical bearing one single bond between the addends. Within ∼50 μs this biradical forms the final adduct featuring a cyclobutane ring. This kinetic behavior is in stark contrast to the closely related photoaddition of two thymine moieties within the DNA. Origins of the differences are discussed.

Tracing the Photoaddition of Pharmaceutical Psoralens to DNA

“…Presumably, this is due to similar spectral signatures of the local triplet state and the triplet biradical. Such similarity was already observed for AMT and AT-DNA [23]. For this system, the intermediary of a triplet biradical found strong support from time-resolved IR spectroscopy.…”

“…Our previous results on the furan side photo-addition of AMT to AT-DNA [23] showed that this addition proceeds via the local triplet state of AMT and a triplet biradical. The present study indicates that this mechanism also applies to 8-MOP and TMP.…”

“…A broad one is located around 1750 cm −1 as well as between 1480-1440 cm −1 . For the assignment to certain vibrations of the reagents one has to keep in mind, that the IR spectrum of 8-MOP was recorded in deuterated acetonitrile and that the frequencies and transition strengths of the vibrations also differ between intercalated and free psoralen [23]. Negative absorption changes around 1700 cm −1 are probably due to the bleach of carbonyl stretching vibrations of 8-MOP as well as thymine.…”

“…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]. The study addressed the derivative 4 -aminomethyl-4,5 ,8-trimethylpsoralen (AMT) and a DNA double-strand consisting of alternating adenine (A) and thymine (T) bases (AT-DNA in the following).…”

Psoralen Derivatives with Enhanced Potency

“…We cannot exclude that our substituents alter the spectrotemporal properties of psoralen and the quantum yield of DNA photoaddition (42). Diekmann et al have shown that photoaddition of intercalated AMT to thymine proceeds via the triplet state with quantum yield 0.12 (43). Though we have focused on intercalation efficiency as the basis for our molecules' efficacy, triplet quantum yields should be investigated in future studies.…”