Synthesis of DNA Oligomers Containing Modified Uracil Possessing Electron-Accepting Benzophenone Chromophore

Synthesis of DNA Oligomers Containing Modified Uracil Possessing Electron-Accepting Benzophenone Chromophor

Photochemistry of Benzophenone Immobilized in a Major Groove of DNA: Formation of Thermally Reversible Interstrand Cross-link

We here report a highly site and sequence selective formation of an interstrand cross-link of BPU-containing oligomer duplexes. The cross-link was found spontaneously reverted to original oligomers upon heating, providing a new method for the temporary connection of two DNA strands

Chemistry of Sequence-Dependent Remote Guanine Oxidation: Photoreaction of Duplex DNA Containing Cyanobenzophenone-Substituted Uridine

Chemistry of Sequence-Dependent Remote Guanine Oxidation:  Photoreaction of Duplex DNA Containing Cyanobenzophenone-Substituted Uridin

Design of a Hole-Trapping Nucleobase: Termination of DNA-Mediated Hole Transport at <i>N</i>²-Cyclopropyldeoxyguanosine

Design of a Hole-Trapping Nucleobase:  Termination of DNA-Mediated Hole Transport at N2-Cyclopropyldeoxyguanosin

Modulation of DNA-Mediated Hole-Transport Efficiency by Changing Superexchange Electronic Interaction

Modulation of DNA-Mediated Hole-Transport Efficiency by Changing Superexchange Electronic Interactio

Affinity Labeling of a Single Guanine Bulge

We have developed a conceptually new method for the selective labeling of duplex DNA containing a guanine bulge with a masked form of fluorescent 2-amino-1,8-naphthyridine. A naphthyridine derivative 2 tethering DNA-alkylating epoxide was synthesized from (S)-epichlorohydrin and naphthyridine derivative 1, which selectively binds to the guanine bulge duplex. HPLC analysis of the labeling reaction of bulge duplex d(GTT GTGTTG GA)/d(CAA CA A ACC T) (TGT/A_A) with 2 showed a formation of 2−TGT adduct for the guanine bulge. The reaction proceeded for the guanine bulge and a reduced efficiency for the cytosine bulge, but not at all for adenine and thymine bulges. The site of covalent bond formation in 2−TGT was unambiguously identified at the guanine two bases away from the bulge by the use of MALDI-TOF MS analysis of the oligomer fragments produced by strand scission. The labeling reaction was also observed for the guanine bulge flanking two G−C base pairs (CGC/G_G), producing a 2:1 adduct (2·2-CGC). Upon hydrolysis of 2−TGT and 2·2-CGC with concentrated hydrogen chloride, a release of fluorescent 2-aminonaphthyridine from the adduct was clearly detected, verifying a concept of an affinity labeling of the guanine bulge with a masked fluorescent chromophore. The affinity labeling targeting of the guanine bulge is a conceptually novel method for the postsynthetic labeling of DNA. Hybridization, to the target sequence, of a probe DNA possessing one extra guanine especially between two cytosines provides a unique site for the labeling by masked fluorophore 2. The technique may have broad application in genetic typing without using a conventional synthesis of fluorescent-labeled DNA oligomers

Inhibitory Effects of Mismatch Binding Molecules on the Repair Reaction of Uracil-Containing DNA

The stable R-loop formed during transcription induces enzyme-mediated deamination of cytosine, and the uracil in the DNA produced activates the base excision repair (BER) pathway. DNA cleavage involved in the BER pathway is thought to be one of the possible causes of trinucleotide repeat instability. Here, we performed an in vitro assay to investigate the effect of a DNA-binding small molecule, naphthyridine carbamate dimer (NCD), on BER enzyme reactions. The gel electrophoretic mobility shift assay (EMSA) and thermal melting analysis revealed the binding of NCD to a 5′-XGG-3′/5′-XGG-3′ triad (X = C or U or apurinic/apyrimidinic site), which is a mimic of a BER enzyme substrate. Polyacrylamide gel electrophoresis (PAGE) of the reaction products of these substrates with hSMUG1 and APE1 enzymes in the presence of NCD showed that NCD interfered with the repair reaction in the 5′-XGG-3′/5′-XGG-3′ triad. These findings would broaden the potential of small molecules in modulating trinucleotide repeat instability

<i>N</i>²-Phenyldeoxyguanosine: Modulation of the Chemical Properties of Deoxyguanosine toward One-Electron Oxidation in DNA

We have shown here that (1) substitution of an exocyclic amino group of dG is effective in modulating the chemical properties of dG toward one-electron oxidation and (2) decomposition of the guanine radical cation was effectively suppressed near dPhG. These results indicate that dPhG is a prototype of nucleosides functioning as an intrinsic antioxidant of duplex DNA toward one-electron oxidation

Mapping of Highest Occupied Molecular Orbitals of Duplex DNA by Cobalt-Mediated Guanine Oxidation

We have examined the oxidation of oligodeoxynucleotides (ODN) containing various guanine (G)-containing sequences with Co(II) ion and benzoyl peroxide (BPO). Sequence-dependent G-cleavage has been observed for double-stranded ODN as revealed by PAGE analysis of the reaction mixture after hot piperidine treatment, whereas non-selective equal G cleavage was observed for single-stranded ODN. The relative rates of sequence-dependent G oxidation were determined by densitometric assay of the DNA cleavage bands. We then performed ab initio calculations of HOMOs of the G-containing sequences with B-form geometry at the HF/6-31G* level. Experimentally observed relative rates of G oxidation matched well with the calculated HOMOs of the G-containing sequences. Thus, the DNA cleavage data obtained from the oxidation of duplex ODNs with Co(II) ion in the presence of BPO correlated nicely with calculated HOMOs, implying that the Co(II) ion is coordinated more strongly to the G having a larger HOMO. These results suggest that the coordination of Co(II) ion to the N7 of guanine base in a duplex DNA is a HOMO-controlled process, in accordance with the previous NMR studies on the sequence-dependent binding of Co(II) ion to the N7 of guanine base of duplex ODN. After performing ab initio calculations of a number of G-containing sequences, we found important general trends that represent the distribution of HOMOs of G bases in B-form DNA. The results of HOMO mapping described here are extremely important for predicting:  (i) which G-sites are more susceptible to electrophilic attack in chemical and biological reactions, such as DNA alkylation by antitumor drugs or mutagens, and (ii) which G-sites are more prone to HOMO−LUMO interactions with DNA-binding drugs and proteins. These results provide a new tool for probing the heterogeneity of DNA sequences

Photoswitchable Molecular Glue for DNA

DNA molecular glue is a small synthetic ligand that can adhere two single-stranded DNAs that do not spontaneously hybridize with each other. For reversible control of DNA hybridization by an external light stimulus, we have developed a photoswitchable molecular glue for DNA. The photoswitchable molecular glue, NCDA, consists of two guanine-recognizing naphthyridine moieties connected with a photochromic azobenzene unit. Azobenzene undergoes a reversible cis/trans isomerization by photoirradiation, which changes the relative orientations and positions of the naphthyridine moieties, resulting into photoswitching of NCDA binding to the DNA containing GG-mismatch. NCDA in the cis configuration binds to a GG-mismatch sequence and induces the formation of the DNA duplex. Using the photoswitchable binding property of NCDA, the hybridization event of two natural unmodified DNAs can be reversibly controlled by an external light stimulus