The Chemical Reactions of DNA Damage and Degradation

Gates, Kent S.

doi:10.1002/9780470120828.ch8

Cited by 21 publications

(23 citation statements)

References 265 publications

(409 reference statements)

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“…Chemistry incompatibility can be due to known reactivities of DNA, 43 such as acid-promoted depurination and concomitant phosphodiester bond cleavage. 44 However, some issues are apparent only after rehearsal, and dissection of the suspect reaction into components can illuminate problematic species and hint at remedies.…”

Section: Resultsmentioning

confidence: 99%

What is a “DNA-Compatible” Reaction?

2016

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DNA-encoded synthesis can generate vastly diverse screening libraries of arbitrarily complex molecules as long as chemical reaction conditions do not compromise DNA’s informational integrity, a fundamental constraint that “DNA-compatible” reaction development does not presently address. We devised DNA-encoded reaction rehearsal, an integrated analysis of reaction yield and impact on DNA, to acquire these key missing data. Magnetic DNA-functionalized sensor beads quantitatively report the % DNA template molecules remaining viable for PCR amplification after exposure to test reaction conditions. Analysis of solid-phase bond forming (e.g., Suzuki-Miyaura cross-coupling, reductive amination) and deprotection reactions (e.g., allyl esters, silyl ethers) guided the definition and optimization of DNA-compatible reaction conditions (> 90% yield, > 30% viable DNA molecules), most notably in cases that involved known (H+, Pd) and more obscure (Δ, DMF) hazards to DNA integrity. The data provide an empirical yet mechanistically consistent and predictive framework for designing successful DNA-encoded reaction sequences for combinatorial library synthesis.

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Section: Resultsmentioning

confidence: 99%

What is a “DNA-Compatible” Reaction?

2016

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“…The two forms of plasmid DNA are then separated using agarose gel electrophoresis, the gel stained with a DNA-binding dye such as ethidium bromide, and the relative amounts of cut and uncut plasmid quantitatively determined by digital imaging analysis. The direct strand breaks (those not requiring thermal or basic workup) monitored in this type of experiment typically arise through abstraction of hydrogen atoms from the 2-deoxyribose backbone of DNA 32,33,66–69…”

Section: Resultsmentioning

confidence: 99%

Initiation of DNA Strand Cleavage by 1,2,4-Benzotriazine 1,4-Dioxide Antitumor Agents: Mechanistic Insight from Studies of 3-Methyl-1,2,4-benzotriazine 1,4-Dioxide

et al. 2008

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The antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ, 1) gains medicinal activity through its ability to selectively damage DNA in the hypoxic cells found inside solid tumors. This occurs via one-electron enzymatic reduction of TPZ to yield an oxygen-sensitive drug radical (2) that leads to oxidatively generated DNA damage under hypoxic conditions. Two possible mechanisms have been considered to account for oxidatively generated DNA damage by TPZ. First, homolysis of the N-OH bond in 2 may yield the well known DNA-damaging agent, hydroxyl radical. Alternatively, it has been suggested that elimination of water from 2 generates a benzotriazinyl radical (4) as the ultimate DNA-damaging species. In the studies described here, the TPZ analogue 3-methyl-1,2,4-benzotriazine 1,4-dioxide (5) was employed as a tool to probe the mechanism of DNA damage within this new class of antitumor drugs. Initially, it was demonstrated that 5 causes redoxactivated, hypoxia-selective oxidation of DNA and small organic substrates in a manner that is completely analogous to TPZ. This suggests that 5 and TPZ damage DNA by the same chemical mechanism. Importantly, the methyl substituent in 5 provides a means for assessing whether the putative benzotriazinyl intermediate 7 is generated following one-electron reduction. Two complementary isotopic labeling experiments provide evidence against the formation of the benzotriazinyl radical intermediate. Rather, a mechanism involving the release of hydroxyl radical from the activated drug radical intermediates can explain the DNA-cleaving properties of this class of antitumor drug candidates.The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ, 1, Scheme 1) is currently undergoing a variety of phase I, II, and III clinical trials for the treatment of human cancers. 1 TPZ gains medicinal activity from its ability to selectively damage DNA in the oxygen-poor (hypoxic) cells found inside solid tumors. [2][3][4][5][6][7][8] This DNA-damage process begins with intracellular enzymatic reduction of TPZ to yield the drug radical intermediate (2 , Scheme 1). [9][10][11][12] In normally-oxygenated cells, 2 undergoes relatively harmless oxidation back to the parent drug (Scheme 1), 9,10,13 while, under hypoxic conditions, the drug radical intermediate 2 leads to oxidatively generated DNA damage including hydroxylation of the nucleobases 22,23 and strand breaks initiated by the abstraction of hydrogen atoms from the sugar-phosphate backbone of DNA. [7][8][9][24][25][26][27][28] In the recent literature, two mechanisms have been considered to explain TPZ-mediated DNA damage. We have presented evidence [22][23][24]26,29 supporting a mechanism involving homolysis of the N-OH bond in the neutral drug radical (2) to yield the mono-N-oxide metabolite 3 and the well known DNA-damaging agent hydroxyl radical (Scheme 1, upper branch). 30 This *To whom correspondence should be addressed: gatesk@missouri.edu; phone: (573) FAX: (573) NIH-PA Author ManuscriptNIH-PA ...

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“…Box 1: Short overview of DNA decay by chemical reactions. For more details, see extensive reviews by 3,14,15 .…”

Section: Expected Decay Processesmentioning

confidence: 99%

“…In this perspective, we describe four principal states of eDNA that are likely in aquatic environments. Based on the presumed chemical behaviour of each state, we discuss how environmental parameters, such as temperature, pH and suspended particles, may influence the conversion of eDNA between states (e.g., 14 ). We briefly review what is known about DNA decay, covered in detail elsewhere 3,12,13 , and summarize what has been observed from experimental studies on eDNA decay in relation to the environmental parameters of temperature and pH.…”

Section: Introductionmentioning

confidence: 99%