Independent Generation and Reactivity of 2‘-Deoxyurid-1‘-yl

Goodman, Brian K.; Greenberg, Marc M.

doi:10.1021/jo951769a

Cited by 58 publications

(43 citation statements)

References 15 publications

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“…2,10 This observation of the majority of piperidine-induced breaks occurring at exactly the same location as immediate breaks, and yielding the same 3A-termini, implies a common mechanistic route for both types of strand break at this site. This is consistent with H-atom abstraction occurring from C1A of the 5A-deoxyribose leading the formation of a deoxyribolactone lesion within the oligonucleotide (5) 11 and a small number of direct breaks possessing phosphate termini, 12,13 although the…”

supporting

confidence: 70%

UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides

Doddridge¹,

Warner²,

Cullis³

et al. 1998

Chem. Commun.

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supporting

confidence: 70%

UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides

Doddridge¹,

Warner²,

Cullis³

et al. 1998

Chem. Commun.

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“…These studies employed a 5′-32 P-labeled 2′-oligodeoxynucleotide containing a single tbutylketone-containing residue 13 that generates a C1′-radical (14) upon photolysis (Scheme 4). 77,78 The 30-mer 2′-oligodeoxynucleotide, 5′-GTCACGTGCTGCA-13-ACGACGTGCTGAGCCT, was photolyzed under anaerobic conditions to generate the C1′radical in the presence of TPZ. 75 The resulting mixture was treated with one of the "fingerprinting" reagents piperidine, dimethylethylenediamine (DMEDA), and 2mercaptoethanol and the products analyzed by gel electrophoresis.…”

Section: Further Evidence For C4′-hydrogen Atom Abstraction: Observatmentioning

confidence: 99%

DNA Strand Damage Product Analysis Provides Evidence That the Tumor Cell-Specific Cytotoxin Tirapazamine Produces Hydroxyl Radical and Acts as a Surrogate for O₂

et al. 2007

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The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) is a clinically promising anticancer agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. It has long been known that, under hypoxic conditions, TPZ causes DNA strand damage that is initiated by the abstraction of hydrogen atoms from the deoxyribose phosphate backbone of duplex DNA, but exact chemical mechanisms underlying this process remain unclear. Here we describe detailed characterization of sugar-derived products arising from TPZ-mediated strand damage. We find that the action of TPZ on duplex DNA under hypoxic conditions generates 5-methylene-2-furanone (6), oligonucleotide 3'-phosphoglycolates (7), malondialdehyde equivalents (8 or 9), and furfural (10). These results provide evidence that TPZ-mediated strand damage arises via hydrogen atom abstraction from both the most hindered (C1') and least hindered (C4' and C5') positions of the deoxyribose sugars in the double helix. The products observed are identical to those produced by hydroxyl radical. Additional experiments were conducted to better understand the chemical pathways by which TPZ generates the observed DNA-damage products. Consistent with previous work showing that TPZ can substitute for molecular oxygen in DNA damage reactions, it is found that, under anaerobic conditions, reaction of TPZ with a discrete, photogenerated C1'-radical in a DNA 2'-oligodeoxynucleotide cleanly generates the 2-deoxyribonolactone lesion (5) that serves as the precursor to 5-methylene-2-furanone (6). Overall, the results provide insight regarding the chemical structure of the DNA lesions that confront cellular repair, transcription, and replication machinery following exposure to TPZ and offer new information relevant to the chemical mechanisms underlying TPZ-mediated strand cleavage.

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“…55–58 2′-Deoxyuridin-1′-yl radical ( 3 ) was generated via Norrish type I photocleavage of 4 . Steady-state and laser flash photolysis experiments supported transformation of the C1′-radical into 2-deoxyribonolactone (L) under aerobic conditions via the carbocation ( 6 ).…”

Section: C1′-radical Generation Reactivity and Related Mechanistimentioning

confidence: 99%

Reactivity of Nucleic Acid Radicals

Greenberg

2016

Advances in Physical Organic Chemistry

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Nucleic acid oxidation plays a vital role in the etiology and treatment of diseases, as well as aging. Reagents that oxidize nucleic acids are also useful probes of the biopolymers’ structure and folding. Radiation scientists have contributed greatly to our understanding of nucleic acid oxidation using a variety of techniques. During the past two decades organic chemists have applied the tools of synthetic and mechanistic chemistry to independently generate and study the reactive intermediates produced by ionizing radiation and other nucleic acid damaging agents. This approach has facilitated resolving mechanistic controversies and lead to the discovery of new reactive processes.

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Independent Generation and Reactivity of 2‘-Deoxyurid-1‘-yl

Cited by 58 publications

References 15 publications

UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides

UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides

DNA Strand Damage Product Analysis Provides Evidence That the Tumor Cell-Specific Cytotoxin Tirapazamine Produces Hydroxyl Radical and Acts as a Surrogate for O₂

Reactivity of Nucleic Acid Radicals

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Independent Generation and Reactivity of 2‘-Deoxyurid-1‘-yl

Cited by 58 publications

References 15 publications

UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides

UV-induced strand break damage in single stranded bromodeoxyuridine-containing DNA oligonucleotides

DNA Strand Damage Product Analysis Provides Evidence That the Tumor Cell-Specific Cytotoxin Tirapazamine Produces Hydroxyl Radical and Acts as a Surrogate for O2

Reactivity of Nucleic Acid Radicals

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DNA Strand Damage Product Analysis Provides Evidence That the Tumor Cell-Specific Cytotoxin Tirapazamine Produces Hydroxyl Radical and Acts as a Surrogate for O₂