Molecular Mechanism of the DNA Sequence Selectivity of 5-Halo-2'-Deoxyuridines as Potential Radiosensitizers

摘要

The 5-halo-2'-deoxyuridines bromodeoxyuridine (BrdU) and iododeoxyuridine (IdU) are well-known photosensitizers for inducing DNA/RNA-protein cross-linking and potential radiosensitizers for radiotherapy of cancer. The dependence of the photosensitivity of BrdU and IdU on the DNA sequence has been well-observed, but it is unknown whether there is a similar DNA sequence selectivity in their radiosensitivity. Here we show a new ultrafast electron transfer (UET) mechanism for the likely DNA sequence dependence of the radiosensitivity of BrdU and IdU. Our femtosecond time-resolved transient laser absorption spectroscopic measurements provide the first real-time observation of the UET reactions of BrdU/ldU with the anion states of adenine and guanine. It is shown that the UET between BrdU and dA~(*-) (dA-) is more effective than that between BrdU and dG(*-). This is related to the recent observation that dG(*-) is highly destructive while dA- is long-lived. This mechanistic understanding may lead to the improvement of BrdU and IdU to achieve sufficient radiosensitizing efficacy and the development of more effective radiosensitizers for clinical uses.