Specific abstraction of the 5'S- and 4'-deoxyribosyl hydrogen atoms from DNA by calicheamicin .gamma.1I

Hangeland, Jon J.; Voss, James J. De; Heath, Julie A.; Townsend, Craig A.; Ding, Wen; Ashcroft, Joseph; Ellestad, George A.

doi:10.1021/ja00049a069

Cited by 116 publications

(66 citation statements)

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“…Our attempts to replace the C3-G21 base pair that flanks the Calicheamicin -yl cleaves both strands of duplex DNA by abstracting hydrogens from partner strands (3,20,21) that correspond to the H5' (pro S) of C5 and H4' of T22 in our DNA hairpin duplex 4. The C3 and C6 pro-radical centers of the enediyne ring are proximal to their expected abstraction sites since we measure average separations of 2.98 A (C3 to H5' of C5) and 3.22 A (C6 to H4' of T22) in our solution structure of the calicheamicin y1I-DNA hairpin duplex 4 complex.…”

Section: (T-c-c-t)d(a-g-g-a) Minor Groove Binding Site and Exhibits mentioning

confidence: 99%

Calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove.

Ikemoto

Kumar

Tao

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Section: (T-c-c-t)d(a-g-g-a) Minor Groove Binding Site and Exhibits mentioning

confidence: 99%

Calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove.

Ikemoto

Kumar

Tao

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…Unlike DNA-cleaving drug molecules (10)(11)(12) and metal complexes (13,14), which show a marked preference for reacting with a particular deoxyribose hydrogen atom, the hydroxyl radical, because of its high reactivity, is expected to be capable of abstracting any of the deoxyribose hydrogens. If the relative reactivity of the hydroxyl radical toward each deoxyribose hydrogen atom were known, a new level of structural detail would be gained in the interpretation of hydroxyl radical footprints.…”

mentioning

confidence: 99%

DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone

Balasubramanian

Pogozelski

Tullius

1998

Proc. Natl. Acad. Sci. U.S.A.

487

458

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Despite extensive study, there is little experimental information available as to which of the deoxyribose hydrogen atoms of duplex DNA reacts most with the hydroxyl radical. To investigate this question, we prepared a set of double-stranded DNA molecules in which deuterium had been incorporated specifically at each position in the deoxyribose of one of the four nucleotides. We then measured deuterium kinetic isotope effects on the rate of cleavage of DNA by the hydroxyl radical. These experiments demonstrate that the hydroxyl radical reacts with the various hydrogen atoms of the deoxyribose in the order 5 H > 4 H > 3 H Ϸ 2 H Ϸ 1 H. This order of reactivity parallels the exposure to solvent of the deoxyribose hydrogens. Our work therefore reveals the structural basis of the reaction of the hydroxyl radical with DNA. These results also provide information on the mechanism of DNA damage caused by ionizing radiation as well as atomic-level detail for the interpretation of hydroxyl radical footprints of DNA-protein complexes and chemical probe experiments on the structure of RNA and DNA in solution.The hydroxyl radical (⅐OH), the quintessential reactive oxygen species, is the mediator of much of the DNA damage caused by ionizing radiation (1). This damage includes strand breaks, which are initiated by abstraction of a deoxyribose hydrogen atom by the hydroxyl radical. DNA strand breaks induced by the hydroxyl radical also form the basis of a widely used method for making footprints of DNA-protein complexes (2, 3) and for studying the structure of DNA (4) and RNA (5) in solution. The key experimental advantage of the hydroxyl radical as a chemical probe is that it effects DNA cleavage with no base-or sequence-specificity (6-8). The hydroxyl radical produces highly detailed footprints that yield information about DNA structure (4, 7) and protein-DNA interactions (3, 8, 9) at single-nucleotide resolution.Mechanistic information on the reaction of the hydroxyl radical with nucleic acids will benefit our understanding of radiation damage to DNA as well as the interpretation of chemical probe experiments. The extensive literature on the radiation chemistry of DNA (1) is a rich source of mechanistic possibilities. Not surprisingly, because of the high reactivity of the hydroxyl radical, a wide spectrum of products has been detected on treatment of the constituents of DNA (nucleic bases, nucleosides, nucleotides, or simple-sequence singlestranded DNA, for example) with ionizing radiation (1). It has been more difficult to conduct similarly detailed experiments on the biologically relevant duplex form of DNA. It is not hard to conceive, though, that the hydroxyl radical might react in a different manner with double-stranded DNA compared with simpler nucleic acid systems because the shape of the double helix would strongly influence the accessibility of the various COH bonds in DNA.Until now, the extent of cleavage at a particular nucleotide in a hydroxyl radical footprinting experiment only could be interpreted at th...

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“…They are used to probe the internal dynamics of oligonucleotides by solid phase 2 H NMR spectroscopy 166,167 . 5'-Deuterated compounds are also used in conformational [168][169][170] and mechanistic [171][172][173] studies. Most of the existing methods do not give a satisfactory level of isomerically pure products and work to develop better methods is in progress in our lab.…”

Section: '-Mono-and Dideuterionucleoside Derivativesmentioning

confidence: 99%

“…The stereoselectivity of deuterium labelling of C5 at the sugar level can be increased via stereoselective photobromination of the 1,5-anhydro compound 100 190 to 101, followed by reductive substitution of the bromine by the use of different deuterated reagents 173,[191][192][193][194] The use of the phenylseleno group as a leaving group for the free-radical deuteration has also been reported [195][196][197][198] …”

Section: '(S)/5'(r)-monodeuterated Nucleosidesmentioning

confidence: 99%

The Synthesis of Deuterionucleosides

Földesi

Trifonova

Kundu

et al. 2000

Nucleosides, Nucleotides and Nucleic Acids

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Specific abstraction of the 5'S- and 4'-deoxyribosyl hydrogen atoms from DNA by calicheamicin .gamma.1I

Abstract: The 1,4-diyl (2) generated from calicheamicin 7/ (1, CLM) by reductive activation1•2 34and rearrangemen ****9t3•4 is believed to initiate DNA cleavage by hydrogen atom abstraction from both strands of the helix to give the reduced form of the drug, CLM e (3).

Cited by 116 publications

References 1 publication

Calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove.

Calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove.

DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone

The Synthesis of Deuterionucleosides

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