Reversible Alkylation of DNA by Quinone Methides

Rokita, Steven E.

doi:10.1002/9780470452882.ch9

Cited by 58 publications

(90 citation statements)

References 76 publications

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“…For example, the quinone methide functionality of QM295 is a powerful Michael acceptor (23). Similarly, the newly described erodoxin (24) is predicted to form thiol adducts by substitution nucleophilic aromatic reaction S N Ar chemistry (supplemental Fig.…”

Section: Discussionmentioning

confidence: 90%

A Small Molecule Inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with Selectively Reversible Thiol Reactivity

Blais

Chin

Zito

et al. 2010

Journal of Biological Chemistry

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Endoplasmic reticulum oxidation 1 (ERO1) is a conserved eukaryotic flavin adenine nucleotide-containing enzyme that promotes disulfide bond formation by accepting electrons from reduced protein disulfide isomerase (PDI) and passing them on to molecular oxygen. Although disulfide bond formation is an essential process, recent experiments suggest a surprisingly broad tolerance to genetic manipulations that attenuate the rate of disulfide bond formation and that a hyperoxidizing ER may place stressed cells at a disadvantage. In this study, we report on the development of a high throughput in vitro assay for mammalian ERO1␣ activity and its application to identify small molecule inhibitors. The inhibitor EN460 (IC 50 , 1.9 M) interacts selectively with the reduced, active form of ERO1␣ and prevents its reoxidation. Despite rapid and promiscuous reactivity with thiolates, EN460 exhibits selectivity for ERO1. This selectivity is explained by the rapid reversibility of the reaction of EN460 with unstructured thiols, in contrast to the formation of a stable bond with ERO1␣ followed by displacement of bound flavin adenine dinucleotide from the active site of the enzyme. Modest concentrations of EN460 and a functionally related inhibitor, QM295, promote signaling in the unfolded protein response and precondition cells against severe ER stress. Together, these observations point to the feasibility of targeting the enzymatic activity of ERO1␣ with small molecule inhibitors.

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Section: Discussionmentioning

confidence: 90%

A Small Molecule Inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with Selectively Reversible Thiol Reactivity

Blais

Chin

Zito

et al. 2010

Journal of Biological Chemistry

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“…Reversible alkylation of G N7 had previously dominated the reaction of bisQMP1 (1) with duplex DNA and dynamic reaction at the C N3 and A N1 were also detected with related QM intermediates 32,43,47 . All of these nucleophiles likely participate in crosslinking, particularly since OD2 contains only a single G and this G is far from the region that could crosslink with OD5.…”

Section: Resultsmentioning

confidence: 99%

“…QMs represent a readily available class of electrophiles capable of both capture and release of various nucleophiles 34 . These species are typically formed only transiently, and yet have found utility in the synthesis of natural products 35,36 , polymers 37 and cytotoxic agents 38 , as well as in functionalization of molecular surfaces 39 .…”

mentioning

confidence: 99%

“…QM formation and regeneration are exquisitely sensitive to electronic effects as evident from the five orders of magnitude separating rate constants for QMs differing by a single substituent 31,40 . Although the reversibility of QM reaction may complicate detection of their adducts formed by xenobiotic metabolism of certain drugs and food additives [41][42][43] , the reversibility has allowed for the construction of target-inducible and site-selective alkylating agents [44][45][46] . Prior model studies indicated that the strongest nucleophiles of DNA (G N7, A N1 and C N3) are alkylated by QMs most readily but their resulting adducts dissipate over time as the weakly nucleophilic nitrogens (G N 2 and A N 6 ) and water began to trap the regenerated QM irreversibly 43,47 .…”

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confidence: 99%

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A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Fakhari

Rokita

2014

Nat Commun

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DNA has previously served as an excellent scaffold for molecular transport based on its noncovalent base pairing to assemble both stationary and mobile elements. Use of DNA can now be extended to transport systems based on reversible covalent chemistry. Autonomous and bipedal-like migration of crosslinking within helical DNA is made possible by tandem exchange of a quinone methide intermediate. In this report, net transport is illustrated to proceed over 10 base pairs. This process is driven towards its equilibrium distribution of crosslinks and consumes neither the walker nor the track irreversibly. Successful migration requires an electron-rich quinone methide to promote its regeneration and a continuous array of nucleophilic sites along its DNA track. Accordingly, net migration can be dramatically influenced by the presence of noncanonical structures within duplex DNA as demonstrated with a backbone nick and extrahelical bulge.

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“…1 Although the partial zwitterionic character of QMs makes them both electrophilic and nucleophilic, their reactivity with nucleophiles is especially important in biological systems. It has been demonstrated that QMs react with amino acids 2 and proteins, 3 and inhibits the action of some enzymes.…”

Section: Introductionmentioning

confidence: 99%

Near-Visible Light Generation of a Quinone Methide from 3-Hydroxymethyl-2-anthrol

et al. 2014

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Excitation of 2-hydroxy-3-(diphenylhydroxymethyl)anthracene (7) to S1 initiates photodehydration giving the corresponding quinone methide (QM) that was detected by laser flash photolysis (LFP) in 2,2,2-trifluoroethanol, TFE (λ = 580 nm, τ = 690 ± 10 ns). The QM decays by protonation, giving cation (λ = 520 nm, τ = 84 ± 3 μs) which subsequently reacts with nucleophiles. The rate constants in the reactions with nucleophiles were determined by LFP, whereas the adducts were isolated via preparative photolyses. The photogeneration of QMs in the anthrol series is important for potential use in biological systems since the chromophore absorbs at wavelengths > 400 nm. Antiproliferative investigations conducted with 2-anthrol derivative 7 on three human cancer cell lines showed higher activity for irradiated cells.

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Reversible Alkylation of DNA by Quinone Methides

Cited by 58 publications

References 76 publications

A Small Molecule Inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with Selectively Reversible Thiol Reactivity

A Small Molecule Inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with Selectively Reversible Thiol Reactivity

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Near-Visible Light Generation of a Quinone Methide from 3-Hydroxymethyl-2-anthrol

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