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

2.50
Hdl Handle:
http://hdl.handle.net/10541/108893
Title:
Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.
Authors:
Lee, C S; Hartley, John A; Berardini, M D; Butler, John; Siegel, David; Ross, David; Gibson, N W
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)
Affiliation:
School of Pharmacy, University of Southern California, Los Angeles 90033.
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
Issue Date:
24-Mar-1992
URI:
http://hdl.handle.net/10541/108893
DOI:
10.1021/bi00126a025
PubMed ID:
1372518
Type:
Article
Language:
en
ISSN:
0006-2960
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLee, C Sen
dc.contributor.authorHartley, John Aen
dc.contributor.authorBerardini, M Den
dc.contributor.authorButler, Johnen
dc.contributor.authorSiegel, Daviden
dc.contributor.authorRoss, Daviden
dc.contributor.authorGibson, N Wen
dc.date.accessioned2010-08-03T08:12:33Z-
dc.date.available2010-08-03T08:12:33Z-
dc.date.issued1992-03-24-
dc.identifier.citationAlteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase. 1992, 31 (11):3019-25 Biochemistryen
dc.identifier.issn0006-2960-
dc.identifier.pmid1372518-
dc.identifier.doi10.1021/bi00126a025-
dc.identifier.urihttp://hdl.handle.net/10541/108893-
dc.description.abstractDT-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)en
dc.language.isoenen
dc.subject.meshAlkylation-
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAscorbic Acid-
dc.subject.meshAziridines-
dc.subject.meshBase Sequence-
dc.subject.meshBenzoquinones-
dc.subject.meshCross-Linking Reagents-
dc.subject.meshDNA-
dc.subject.meshDicumarol-
dc.subject.meshHydrogen-Ion Concentration-
dc.subject.meshLiver-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshNADPH Dehydrogenase-
dc.subject.meshOxidation-Reduction-
dc.subject.meshRats-
dc.titleAlteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.en
dc.typeArticleen
dc.contributor.departmentSchool of Pharmacy, University of Southern California, Los Angeles 90033.en
dc.identifier.journalBiochemistryen
All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.