2. Application of Biomimetic Dehalogenation in Drug Design


(b) Dehalogenation of Halogenated Nucleosides in DNA Repair


Halogenated nucleosides such as 5-bromo-2'-deoxyuridine (BrdUd) and 5-iodo-2'-deoxyuridine (IdUd) are incorporated into DNA of dividing cells during the S-phase of the cell cycle, essentially substituting for thymidine during DNA replication. These compounds are widely used for birth dating human cells and monitoring cell proliferation and, owing to their ability to cross the blood-brain barrier, they are combined with conventional chemotherapy and radiation treatment for cancer in several clinical trials. However, halogenation of nucleobases and nucleotides is associated with DNA damage,

results described by them are important not only for understanding the dehalogenation of halogenated nucleosides in DNA and RNA, but also for the development of novel compounds for DNA modification and repair. Furthermore, this study suggests that selenium compounds may play a broader role in the metabolism of halogenated organic compounds in biology, beyond thyroid hormone deiodination (described in the previous section). As the reactive halogen species (RHS) such as HOX (X = Cl, Br and I) produced by heme peroxidases are known to modify nucleic acids by halogenation at sites of inflammation in vivo, synthetic compounds with dehalogenase activity under physiological conditions can be considered potential candidates for the development of novel anti-inflammatory drugs.

It is known that 5-halouracil (5-XU) can be incorporated into DNA in place of thymine (T). The rare base-pair formation between guanine (G) and 5-XU, which is stabilised by the enol-tautomer of 5-XU, favours the formation of a guanine-cytosine (G-C) pair leading to a mutation in the gene (Figure 14A,B). To understand the effect of other bases on the dehalogenation reactions, Mugesh and coworkers studied the removal of halogen in 5-XU by the diselenol shown in Figure 13 in the presence of different concentrations of adenine and guanine (Figure 14C and 14D). For 5-IU, the base-pair formation with adenine as well as guanine enhances the rate of deiodination, indicating that the hydrogen bonding facilitates the halogen bonding between the selenium and iodine atom. While the addition of adenine to 5-BrU remarkably enhances the rate of debromination, no such enhancement was observed for guanine. In fact, the rate of debromination at higher concentration of guanine was slightly lower than that of the control rate, indicating that the stabilization of enol form of 5-BrU disfavours the addition-elimination reactions (Mondal, S.; Manna, D.; Mugesh, G. Angew. Chem. Int. Ed. 2015, Click here for the article).

Figure 14. (A) Mutation in DNA due to incorporation of 5-XU. The base-pair between the enol form of 5-XU and guanine leads to the formation of guanine-cytosine (G-C) base-pair. (C) Formation of base-pairs between 5-XU, adenine and guanine. Effect of adenine (A) and guanine (G) on the deiodination of 5-IU (D) and debromination of 5-BrU (E).


Mondal, S.; Manna, D.; Mugesh, G.

Angew. Chem. Int. Ed. 2015, doi/10.1002/ anie.201503598.

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mutagenesis, cytotoxicity, carcinogenesis and loss of genome integrity. The dehalogenation of halo-uracil moiety is a key process in DNA repair as the resulting uracil base can be removed from the DNA by uracil-DNA glycosylases via the base- excision repair (BER) pathway. It has been shown that thymidylate synthase (TSase), a key enzyme involved in the biosynthesis of 2′-deoxythymidine-5′-monophosphate (dTMP) from 2′-deoxyuridine-5′-monophosphate (dUMP), can mediate the dehalogenation of 5-bromo- and 5-iodo-2′-deoxyuridine-5′-monophosphate (BrdUMP and IdUMP) to 2′-deoxyuridine-5′-monophosphate (dUMP) in the presence of thiols (Figure 12).

Figure 12. (A) Biosynthesis of dTMP from dUMP and dehalogenation of 5-halo-2′-deoxyuridine-5′-monophosphate by Tsase (THF = tetrahydrofolate). (B) The active site of TSase from L. casei showing the binding of dUMP and the presence of a cysteine residue that acts as a nucleophile (PDB: 2TDM).

Very recently, we described the first example of a selenium-mediated dehalogenation of halogenated nucleobases and nucleosides. While the mechanism for the debromination is different from that of deiodination, the halogen bond-mediated deiodination provides a simple and efficient method for the removal of iodine from iododeoxyuridine (IdUd) and iodouridine (IUd) without affecting the deoxyribose or ribose moiety at physiologically relevant conditions (Figure 13). The