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    Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.

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    Authors
    Lee, C S
    Hartley, John A
    Berardini, M D
    Butler, John
    Siegel, David
    Ross, David
    Gibson, N W
    Affiliation
    School of Pharmacy, University of Southern California, Los Angeles 90033.
    Issue Date
    1992-03-24
    
    Metadata
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    Abstract
    DT-diaphorase (DTD) mediated reduction of a series of 2,5-bis-substituted-3,6-diaziridinyl-1,4-benzoquinones was found to increase the level of DNA interstrand cross-linking (ISC) formed at neutral pH with an enhancement observed as the pH was decreased to 5.8. The analogues used were symmetrically alkyl-substituted carbamoyl ester analogues of AZQ (D1-D7), 3,6-diaziridinyl-1,4-benzoquinone (DZQ), the 2,5-dimethyl derivative (MeDZQ), and a 2,5-bis[(2-hydroxyethyl)amino] analogue (BZQ). At pH 5.8, the level of DNA ISC induced by enzymatic reduction was as follows: DZQ greater than MeDZQ much greater than D1 (methyl) greater than D3 (n-propyl) greater than D2 (AZQ; ethyl) greater than D5 (n-butyl) greater than D7 (sec-butyl) greater than D4 (isopropyl) D6 greater than (isobutyl). A similar trend was observed at pH 7.2. The level of DNA ISC induced by BZQ, which is not a substrate for DTD, was not increased by enzymatic reduction. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the DNA ISC induced by these quinones upon enzymatic reduction. MeDZQ and DZQ reacted with guanines, as measured by Maxam and Gilbert sequencing, with a sequence selectivity similar to that of the nitrogen mustard class of antitumor agents. Enzymatic reduction of DZQ and MeDZQ by DTD was found to alter their sequence-selective alkylation. Reduced DZQ showed enhanced guanine alkylation in 5'-GC-3' sequences and new sites of adenine alkylation in 5'-(A/T)AA-3' sequences. Reduced MeDZQ only showed new sites of adenine alkylation at 5'-(A/T)AA-3' sequences but no enhancement of guanine alkylation. The new sites of adenine alkylation were found to be inhibited in the presence of magnesium and rapidly converted into apurinic sites.(ABSTRACT TRUNCATED AT 250 WORDS)
    Citation
    Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase. 1992, 31 (11):3019-25 Biochemistry
    Journal
    Biochemistry
    URI
    http://hdl.handle.net/10541/108893
    DOI
    10.1021/bi00126a025
    PubMed ID
    1372518
    Type
    Article
    Language
    en
    ISSN
    0006-2960
    ae974a485f413a2113503eed53cd6c53
    10.1021/bi00126a025
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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    Related articles

    • Relationship between DT-diaphorase-mediated metabolism of a series of aziridinylbenzoquinones and DNA damage and cytotoxicity.
    • Authors: Gibson NW, Hartley JA, Butler J, Siegel D, Ross D
    • Issue date: 1992 Sep
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    • Authors: Hartley JA, Berardini M, Ponti M, Gibson NW, Thompson AS, Thurston DE, Hoey BM, Butler J
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